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Biomedical subjects

Henry L Halliday

Publications and source records attributed to Henry L Halliday.

At least 19 recordsLinked to original sources
PubMed2006

Influence of maternal diabetes mellitus on fetal iron status.

OBJECTIVE: To determine the effects of maternal diabetes on fetal iron status using serum transferrin receptors (STfR) and their ratio to ferritin (TfR-F index) in cord blood. METHODS: Iron, ferritin, erythropoietin, STfR and haemoglobin concentration were measured and TfR-F index calculated in 97 maternal/cord blood pairs. Forty-nine women had type 1 diabetes (diagnosed before pregnancy) and these were compared with forty-eight non- diabetic controls. The women with type 1 diabetes were recruited consecutively from attendance at the joint antenatal endocrine clinic while the control group of women was recruited from consecutive attendance at the remaining antenatal clinics. RESULTS: The infants of the diabetic women had significantly lower levels of ferritin (47 vs 169 mug/l; p<0.01) and higher STfR (17.4 vs 12.9 mg/l; p<0.01) and TfR-F index (10.4 vs 5.8; p<0.01) than controls. They were also significantly more acidotic at birth (7.25 vs 7.30; p<0.01), were born at an earlier gestation (36.7 vs 39.7 weeks; p<0.01) and had higher z Scores for weight (0.53 vs 0.02; p = 0.016). CONCLUSIONS: Maternal diabetes causes depletion of fetal iron stores and is associated with higher fetal iron demands as indicated by higher STfR level and TfR-F index in cord blood.

Birth Weight↗
PubMed2006

Recent clinical trials of surfactant treatment for neonates.

OBJECTIVE: To search for recent clinical trials of neonatal surfactant treatment and report their findings. METHODS: Recent was defined as published between 2000 and 2005. An online search on PubMed was made on 30th December 2005 using the following terms: surfactant treatment, clinical trials and neonate, with limits of years 2000 to 2005 and age - newborn from birth to 1 month. Randomised clinical trials (RCTs) and systematic reviews of RCTs were prioritised and studies in children and animals were excluded from further analysis. RESULTS: 175 papers were found in this search. Only about half of these papers were directly related to some aspect of surfactant treatment and of these just over one-half were either RCTs or systematic reviews of RCTs. Of the 34 RCTs of surfactant treatment, 3 were excluded as they involved children or animals rather than neonates. Twenty-nine trials studied preterm babies with respiratory distress syndrome (RDS) and 2 were for meconium aspiration syndrome (MAS) in term infants. The median sample sizes of these studies were RDS (92, range 19-1,361) and MAS (42, range 22-61). Eighteen of the RDS trials compared two or more surfactant preparations, the most frequently studied being Curosurf and Survanta but altogether 11 different surfactants were compared. These new RCTs need to be analysed by meta-analyses in systematic reviews. Twelve systematic reviews were found and these demonstrated the superiority of prophylactic over selective use of surfactant in babies <30 weeks, natural over synthetic surfactant and the absence of an increase in long-term developmental sequelae. Surfactant for MAS may reduce the severity of respiratory illness and the need for extracorporeal membrane oxygenation. Of the non-randomised trials' novel delivery methods, failure to use evidence-based guidelines and the benefit of surfactant for babies <25 weeks were the most interesting. CONCLUSIONS: Surfactant remains one of the most effective and safest interventions in neonatology. Prophylactic natural surfactant seems to be the most evidence-based treatment for babies <30 weeks. Of the newer synthetic surfactants, only Surfaxin has been compared with currently used surfactants and systematic reviews are needed to establish if it has a role in treatment of RDS. The improvement in outcome for babies <25 weeks has been due to a number of interventions: prenatal steroids, prenatal antibiotics and postnatal surfactant. Clinical trials of surfactant replacement in the neonate continue to be published with remarkable frequency.

Clinical Trials as Topic↗
PubMed2006

Neurodevelopmental and respiratory follow-up results at 7 years for children from the United Kingdom and Ireland enrolled in a randomized trial of early and late postnatal corticosteroid treatment, systemic and inhaled (the Open Study of Early Corticosteroid Treatment).

OBJECTIVES: The goals were to compare early school-age neurodevelopmental and respiratory outcomes for children who were treated with either early (<3 days) or delayed selective (>15 days) postnatal corticosteroid therapy and to compare systemic dexamethasone treatment with inhaled budesonide treatment. METHODS: One hundred twenty-seven (84%) of 152 survivors from the United Kingdom and Ireland who were recruited to the Open Study of Early Corticosteroid Treatment, a randomized trial of inhaled and systemic corticosteroid therapy to prevent chronic lung disease, were traced and assessed at a median age of 7 years. Outcome measures were level of disability, presence of cerebral palsy, cognitive ability, behavioral difficulties and competencies, growth, and respiratory symptoms. Results were adjusted for potential confounding variables (gestational age, birth weight, gender, prenatal steroid therapy, method of delivery, Apgar score at 5 minutes, and Clinical Risk Index for Babies score). RESULTS: There were no significant differences among the treatment groups in cognitive ability, behavioral competencies or difficulties, overall disability rates, cerebral palsy, combined outcomes of death or cerebral palsy and death or moderate/severe disability, growth, respiratory morbidity, or diastolic blood pressure. Those assigned to dexamethasone were more likely to have high systolic blood pressure and to have a diagnosis of asthma than were those assigned to budesonide. CONCLUSIONS: Although postnatal steroid therapy has been associated with poor long-term outcomes, this study failed to show significant differences in cognitive function between dexamethasone- and budesonide-allocated groups. There may be increased systolic blood pressure and a greater likelihood of developing asthma in childhood after postnatal dexamethasone treatment.

Administration, Inhalation↗
PubMed2006

HOX genes: seductive science, mysterious mechanisms.

HOX genes are evolutionarily highly conserved. The HOX proteins which they encode are master regulators of embryonic development and continue to be expressed throughout postnatal life. The 39 human HOX genes are located in four clusters (A-D) on different chromosomes at 7p15, 17q21 [corrected] 12q13, and 2q31 respectively and are assumed to have arisen by duplication and divergence from a primordial homeobox gene. Disorders of limb formation, such as hand-foot-genital syndrome, have been traced to mutations in HOXA13 and HOXD13. Evolutionary conservation provides unlimited scope for experimental investigation of the functional control of the Hox gene network which is providing important insights into human disease. Chromosomal translocations involving the MLL gene, the human homologue of the Drosophila gene trithorax, create fusion genes which exhibit gain of function and are associated with aggressive leukaemias in both adults and children. To date 39 partner genes for MLL have been cloned from patients with leukaemia. Models based on specific translocations of MLL and individual HOX genes are now the subject of intense research aimed at understanding the molecular programs involved, and ultimately the design of chemotherapeutic agents for leukaemia. Investigation of the role of HOX genes in cancer has led to the concept that oncology may recapitulate ontology, a challenging postulate for experimentalists in view of the functional redundancy implicit in the HOX gene network.

Animals↗
PubMed2005

History of surfactant from 1980.

The first successful trial of surfactant treatment for respiratory distress syndrome (RDS) was reported in 1980. Since then there have been numerous randomised trials demonstrating first, the efficacy of surfactant treatment in reducing pulmonary air leaks and increasing survival and second, assessing various other aspects of therapy. These studies show that multiple doses may be needed if surfactant is used to treat established RDS but early or prophylactic treatment is superior for infants with gestational ages less than 30 weeks. Natural surfactants (containing proteins) are more effective than synthetic products (protein free), the latter now being infrequently used. Natural surfactants vary and should not be considered to be equivalent in their effects. A porcine surfactant (poractant alfa) acts more rapidly than a bovine preparation (beractant) in infants with moderate to severe RDS. A meta-analysis of 5 comparative studies suggests that a dose of 200 mg/kg of poractant alfa is associated with lower mortality compared with 100 mg/kg of beractant. Chronic lung disease remains a problem but it is hoped that early treatment with surfactant combined with extubation to continuous positive airway pressure will reduce this complication of prematurity. The newer synthetic surfactants, containing analogues of surfactant protein B or C, have undergone some trials for treatment of RDS but comparative studies which have just been published do not show that they are superior to existing natural surfactants. However, as they are more resistant to inactivation they may have a role in treatment of adult or acute RDS. The last 25 years have seen a large increase in basic science research on surfactants with determination of the structure and function of the four surfactant proteins probably being the most important advances. Future studies will focus on widening the indications for surfactant treatment, developing non-invasive means of administration and assessing the role of the newer synthetic surfactants.

Animals↗
PubMed2005

Impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: effect modification by risk for chronic lung disease.

OBJECTIVE: In preterm infants, chronic lung disease (CLD) is associated with an increased risk for cerebral palsy (CP). However, systemic postnatal corticosteroid therapy to prevent or treat CLD, although effective in improving lung function, may cause CP. The objective of this study was to determine the effect of systemic postnatal corticosteroid treatment on death and CP and to assess any modification of effect arising from risk for CLD. METHODS: Randomized, controlled trials of postnatal corticosteroid therapy for prevention or treatment of CLD in preterm infants that reported rates of both mortality and CP were reviewed and their data were synthesized. Twenty studies with data on 1721 randomized infants met eligibility criteria. The relationship between the corticosteroid effect on the combined outcome, death or CP, and the risk for CLD in control groups was analyzed by weighted meta-regression. RESULTS: Among all infants who were randomized, a significantly higher rate of CP after corticosteroid treatment (typical risk difference [RD]: 0.05; 95% confidence interval [CI]: 0.02, 0.08) was partly offset by a nonsignificant reduction in mortality (typical RD: -0.02; 95% CI: -0.06 to 0.02). Consequently, there was no significant effect of corticosteroid treatment on the combined rate of mortality or CP (typical RD: 0.03; 95% CI: -0.01 to 0.08). However, on meta-regression, there was a significant negative relationship between the treatment effect on death or CP and the risk for CLD in control groups. With risks for CLD below 35%, corticosteroid treatment significantly increased the chance of death or CP, whereas with risks for CLD exceeding 65%, it reduced this chance. CONCLUSIONS: The effect of postnatal corticosteroids on the combined outcome of death or CP varies with the level of risk for CLD.

Adrenal Cortex Hormones↗
PubMed2005

Management of bronchopulmonary dysplasia in infants: guidelines for corticosteroid use.

Bronchopulmonary dysplasia (BPD) is a common cause of morbidity and mortality in preterm neonates and at present its management is unclear. Over the past three decades there has been a growing use of corticosteroids in the postnatal period; first for the treatment and then, more recently, for the prevention of BPD. The first published use of corticosteroids to treat neonatal lung disease was in 1956; however, it was only in the 1980s and 1990s that their use in neonates became commonplace. Concerns about their long-term neurodevelopmental consequences arose in the late 1990s when follow-up of randomised controlled trials indicated an increased risk of cerebral palsy after postnatal dexamethasone exposure. Dexamethasone has been the most frequently used corticosteroid in neonatal units, although others, including hydrocortisone, prednisolone and methylprednisolone, have been studied, as have inhaled corticosteroids. Systematic reviews indicate that systemic corticosteroids improve respiratory function in the short term and expedite extubation in preterm neonates. However, there is a high risk of hypertension, hyperglycaemia and gastrointestinal complications in corticosteroid-treated neonates and, if administered in the first 4 days of life, an association with long-term neurodevelopmental delay. There should be emphasis on prevention of BPD by reducing the risk factors associated with its development. There is no role for use of corticosteroids in the first 4 days of life as the high risk of long-term adverse effects outweighs any likely short-term benefits. Corticosteroid use should be limited to exceptional clinical circumstances, such as a ventilator-dependent infant after the second week of life who cannot be weaned from ventilation and whose condition is worsening. If used, they should be prescribed at the lowest effective dose for the shortest possible time. Further randomised trials of low-dose corticosteroids given after the first week of life are warranted and should assess both short- and long-term outcomes.

Adrenal Cortex Hormones↗
PubMed2005

Modeling and remodeling of the lung in neonatal chronic lung disease: implications for therapy.

Neonatal chronic lung disease (CLD) is the major long-term pulmonary complication of preterm birth affecting about 20% of infants who need mechanical ventilation. CLD is the result of abnormal repair processes following inflammatory lung injury that lead to remodeling of the lung. Inflammation may be initiated by a variety of stimuli including mechanical ventilation, oxygen toxicity and infection. The resultant neutrophil chemotaxis and degranulation leads to the release of enzymes such as matrix metalloproteinases that can cause proteolysis of the lung extracellular matrix. Abnormal healing with remodeling leads to poorly compliant lungs with reduced capacity for gas exchange. Drugs can influence the normal process of lung modeling or remodeling. Fetal lung development can be influenced by glucocorticosteroids and inflammation. Both can cause abnormal lung modeling with fewer, larger alveoli and accelerated lung maturation, which confers benefits in terms of reduced morbidity and mortality from respiratory distress syndrome but potentially increases the risk of subsequent lung injury. Antioxidants, such as retinol (vitamin A), administered post-natally may reduce the effects of oxidative stress leading to a modest reduction in CLD but they require repeated intramuscular injections. Postnatal glucocorticosteroid therapy can modify the lung inflammatory response and reduce CLD but it can also have detrimental effects on the developing brain and lung, thereby creating a clinical dilemma for neonatologists. Proteinase inhibitors may be a rational therapy but more research is needed before they can be accepted as a treatment for preterm neonates.'Modeling' is defined as planning or forming that follows a set pattern. The term is used to describe the normal process of lung growth and development that culminates in mature branching alveolar air spaces surrounded by a network of capillaries. Normal lung modeling occurs under a variety of genetic and hormonal influences that can be altered, leading to abnormal patterns of growth. 'Remodeling' is defined as altering the structure of or re-making and, in the case of the lung, is used to describe the abnormal patterns of lung growth that occur after lung injury. Modeling and remodeling of the lungs occur to an extent throughout life but never more rapidly than during the fetal and early neonatal periods, and factors that influence this process may lead to development of neonatal CLD. Some of the factors involved in normal and abnormal lung modeling and inflammation and glucocorticosteroid-induced remodeling in the perinatal period, in the context of neonatal CLD, are reviewed with considerations of how various drugs may influence these processes.

Chronic Disease↗
PubMed2004

Evidence-based neonatal care.

Randomized controlled trials were introduced into neonatal care in the 1950s when high inspired oxygen concentrations were discovered to be the cause of an epidemic of blindness in preterm babies due to retinopathy of prematurity. Systematic reviews of many randomized controlled trials were published in an important textbook in 1992, 'Effective Care of the Newborn Infant', which was the starting point for the Neonatal Module of the Cochrane Collaboration. The 171 systematic reviews of interventions in neonatology published in the Cochrane Library provide evidence for neonatal care in many areas of the speciality. Some areas, such as management of respiratory distress with surfactant and assisted ventilation, are well covered by reviews, but others, such as resuscitation at birth and management of jaundice, are much less evidence based. Most of the systematic reviews deal with neonatal care in the developed world, and there are only a few of interest to carers in the developing world.

Developing Countries↗
PubMed2004

Postnatal steroids and chronic lung disease in the newborn.

INTRODUCTION: Chronic lung disease (CLD) represents a condition of persistent inflammation within the airways which may have its origin either in utero or after birth. Corticosteroids, because of their anti- inflammatory actions, have been used to modify the course of CLD. There have been almost 40 randomised controlled trials of postnatal dexamethasone and 12 of inhaled steroids. METHODS: Systematic reviews of randomised controlled trials of postnatal steroids (either systemic or inhaled) for CLD in the Cochrane Library were evaluated as a guide to clinical practice. Results are presented as relative risks (RR), numbers needed to treat (NNT) or harm (NNH) each with 95% confidence intervals (CI). RESULTS: Postnatal dexamethasone reduces the incidence of CLD and facilitates earlier extubation but with early treatment there are serious long-term neurological adverse effects. Inhaled steroids used early (<2 wk) reduce the need for later dexamethasone (RR 0.78; 0.62-0.99 and NNT 11; 6-125). Inhaled steroids used late (>2 wk) increase the chances of extubation (RR 0.38; 0.20-0.72 and NNT 3; 2-6) and improve ventilator settings and lung mechanics. There appear to be no serious adverse effects of inhaled steroids but comparative studies suggest that dexamethasone acts more rapidly. CONCLUSIONS: Postnatal dexamethasone at currently recommended doses should be avoided. Lower dose dexamethasone or inhaled steroids might be indicated for ill, ventilator-dependent infants with CLD after the age of 2 weeks. More trials of inhaled steroids should be undertaken and these should include long-term follow-up.

Chronic Disease↗
PubMed2004

Use of steroids in the perinatal period.

INTRODUCTION: Corticosteroids can be used prenatally to mature the fetal lungs and postnatally to treat or prevent chronic lung disease (CLD). Randomised controlled trials have been performed to evaluate the benefits and risks of perinatal corticosteroid therapy. METHODS: Systematic reviews of randomised controlled trials of prenatal and postnatal corticosteroids in the Cochrane Library were examined to determine the cost-benefit ratios of treatment. Outcomes are given as numbers needed to treat (NNT) or numbers needed to harm (NNH) with 95% confidence intervals (CI). RESULTS: Prenatal corticosteroids reduce the risk of RDS (NNT 11; 95% CI 9-16), surfactant use (NNT 9; 95% CI 5-62), intraventricular haemorrhage (NNT 9; 95% CI 6-19) and neonatal mortality (NNT 23; 95% CI 16-42). There are no short-term or long-term adverse effects of a single course of prenatal betamethasone. However, repeated courses of prenatal steroids could be harmful and should be avoided outside of a randomised controlled trial. Postnatal corticosteroids can be used to prevent CLD (early use) or to treat it (late use). Beneficial effects include earlier extubation (typical NNT 5; 95% CI 4-10), reduced CLD (typical NNT 10; 95% CI 8-17) and avoidance of late steroids (NNT 7; 95% CI 6-10). However, there are significant adverse short-term effects such as hyperglycaemia (typical NNH 8; 95% CI 6-10), hypertension (typical NNH 10; 95% CI 8-14). Hy- pertrophic cardiomyopathy (typical NNH 5; 95% CI 4-11), gastrointestinal bleeding (typical NNH 17; 95% CI 11-33) and growth failure (NNH 2; 95% CI 1-2). More important are long-term adverse effects of cerebral palsy (typical NNH 8; 95% CI 6-17), developmental delay (typical NNH 7; 95% CI 4-33) and abnormal neurological examination (typical NNH 4; 95% CI 2-14). These adverse effects are more pronounced with early (<96 h) treatment but probably also occur when steroids are given later in the postnatal period. CONCLUSIONS: A single course of prenatal betamethasone has clear benefits for the fetus who is likely to be born preterm but repeated courses may be harmful. Postnatal steroids should be avoided if at all possible. They might be indicated in very low doses for ventilator-dependent infants who might otherwise die without them.

Adrenal Cortex Hormones↗
PubMed2004

What interventions facilitate weaning from the ventilator? A review of the evidence from systematic reviews.

INTRODUCTION: Mechanical ventilation is life saving for many very preterm babies but prolonged use can have adverse effects increasing the risk of subglottic injury and chronic lung disease (CLD). Shorter ventilation should reduce these risks and a number of interventions have been tested to facilitate earlier extubation. METHODS: The Cochrane Library was searched for systematic reviews of randomised controlled trials of interventions to facilitate extubation and reduce post-extubation atelectasis. These interventions included nasal continuous positive airway pressure (CPAP), nasal intermittent positive pressure ventilation (NIPPV), chest physiotherapy, intravenous dexamethasone and methylxanthine treatment. Outcomes are given as numbers needed to treat (NNT) with 95% confidence intervals (CI). RESULTS: Nasal CPAP reduces the incidence of adverse effects after extubation including failure (NNT 6; 95% CI 4-15) and CLD at 28 days (NNT 6; 95% CI 3-22). NIPPV is superior to nasal CPAP at preventing extubation failure (NNT 3; 95% CI 2-5). Chest physiotherapy after extubation does not reduce alveolar atelectasis but it decreases need for re-intubation (NNT 6; 95% CI 4-23). Chest physiotherapy needs to be given 1-2 hourly to obtain this effect. Intravenous dexamethasone reduces the need for re-intubation (NNT 6; 95% CI 3-250) but adverse effects preclude its routine use. Methylxanthines also improve the chances of successful extubation (NNT 4; 95% CI 2-7) and the effect is greatest in infants <1000g birthweight and <7 days postnatal age (NNT 2; 95% CI 1-8). CONCLUSIONS: Nasal CPAP, NIPPV and methylxanthines are evidence-based treatments to facilitate weaning and extubation of preterm infants but only the first 2 can be recommended for routine use. Chest physiotherapy and dexamethasone may be effective but should not be used routinely because of serious adverse effects.

Humans↗
PubMed2004

Effects of glucocorticoids on fetal and neonatal lung development.

Antenatal glucocorticoids have been used for 30 years to induce maturation of preterm fetal lungs. Stimulation of the pulmonary surfactant system has been regarded as the most important effect of antenatal glucocorticoids; however, as these drugs alter the expression of a large number of genes they affect the maturation of the lung in several other ways. Antioxidant enzyme production, lung fluid absorption and alveolar development are all affected by glucocorticoids administered in the perinatal period. There is evidence that glucocorticoids induce genes associated with the synthesis of surfactant proteins, fatty acid synthase, the epithelial sodium channel and the membrane protein sodium/potassium ATPase as well as several antioxidant enzymes including catalase, glutathione peroxidase and two superoxide dismutases. Glucocorticoids also increase the expression of vascular endothelial growth factor, which may inhibit alveolarization and lead to abnormally large alveoli. The use of both antenatal and postnatal glucocorticoids has increased in the past decade. However, as concerns about possible long-term effects have arisen, the mechanisms of how glucocorticoids alter the structure and function of the lungs needs to be determined to allow the development of more specific agents in the treatment of respiratory distress syndrome.

Betamethasone↗
PubMed2003

Corticosteroids in the prevention and management of bronchopulmonary dysplasia.

Corticosteroids were first prescribed for preterm neonates to treat respiratory distress syndrome, but they were found to have no beneficial effect in this disorder. About 20 years ago, dexamethasone was first used to treat infants with bronchopulmonary dysplasia who were ventilator dependent after the age of 3 weeks. There were short-term benefits, with an improvement in lung function and a facilitation of endotracheal extubation. During the 1990s, corticosteroid treatment, mainly with dexamethasone in relatively high doses, became very common in neonatal intensive care units. Towards the end of the decade, however, follow-up studies provided evidence of abnormal neurodevelopment, especially in infants treated early (<4 days) with dexamethasone. The precise cause of these neurodevelopmental problems is unclear, but until further evidence has been obtained, the early use of dexamethasone cannot be recommended for preterm infants. This review attempts to provide evidence-based guidelines for postnatal steroid therapy in the management of chronic lung disease.

Adrenal Cortex Hormones↗
PubMed2003

Chorioamnionitis and increased neonatal lung lavage fluid matrix metalloproteinase-9 levels: implications for antenatal origins of chronic lung disease.

OBJECTIVE: Matrix metalloproteinase-9 (MMP-9) degrades type IV collagen, the major constituent of lung basement membrane. We studied the effects of chorioamnionitis and antenatal corticosteroids on bronchoalveolar lavage (BAL) fluid levels of MMP-9, and its inhibitor, TIMP-1 in preterm infants. STUDY DESIGN: A prospective study was performed on serial BAL samples from 79 ventilated preterm infants at less than 33 weeks' gestation, 18 of whom were from pregnancies complicated by chorioamnionitis. MMP-9 levels were measured by gelatin zymography and TIMP-1 by enzyme-linked immunosorbent assay, and the median value for each infant was calculated. The presence and severity of chorioamnionitis were defined histologically. RESULTS: BAL fluid MMP-9 levels were higher in preterm infants in the chorioamnionitis group (86 [29-518] vs 13 [3-43] ng/mL, P =.001), and levels increased stepwise with the increasing severity of chorioamnionitis. Antenatal corticosteroids had no effect on median MMP-9 levels. Infants in the chorioamnionitis group were more likely to have chronic lung disease (CLD) develop (55% vs 28%, P <.05). TIMP-1 levels were no different between groups. CONCLUSION: Chorioamnionitis is associated with increased lung type IV collagenase levels in the ventilated preterm infant. Antenatal lung inflammation with up-regulation of MMP-9 may be important in the pathogenesis of CLD.

Bronchoalveolar Lavage Fluid↗