The use of surfactants in 2009.

Surfactant replacement therapy has been available for about 25 years, revolutionising neonatal respiratory care after its introduction in the 1980s. Along with antenatal steroids, surfactants improve survival for preterm babies and they are now recommended routinely as early in the course of respiratory distress syndrome (RDS) as possible. Prophylactic treatment, although appearing ideal, exposes some babies who might manage perfectly well on continuous positive airway pressure (CPAP) to intubation and ventilation, which may increase the risk of bronchopulmonary dysplasia. Recent studies attempt to determine the optimal balance between avoiding ventilation by using CPAP and giving surfactant in a timely fashion to babies with RDS. Surfactants are also used for conditions other than RDS, such as meconium aspiration, pulmonary haemorrhage and pneumonia, although the evidence base for their use in these indications is much weaker. Recently, surfactants have been used to deliver steroids directly to the lungs and this seems to be a promising technique worthy of further study. Finally, the quest goes on to develop a synthetic product that can match the effects of animal derived natural surfactants and could be produced at lower cost.

A dose response study of inhaled nitric oxide in hypoxic respiratory failure in preterm infants.

BACKGROUND: Inhaled nitric oxide (iNO) is used widely in newborn infants with hypoxic respiratory failure, despite the known and theoretical toxicity of iNO, and a relative lack of information about appropriate doses. AIM: To determine whether a dose-response relationship existed for iNO in preterm infants. DESIGN: A four-period, four-dose, cross-over design was used with iNO given for 15 min in a randomised sequence in concentrations of 5, 10, 20 and 40 parts per million (ppm), with a minimum 5 min wash-out period. Data on ventilatory, blood gas and other physiological measurements were recorded before and at the end of each period. The relationship of clinical response with iNO dose and period was analysed using multivariate regression. SUBJECTS: Infants with gestational age < 34 weeks and < 28 days postnatal age with hypoxic respiratory failure were recruited. OUTCOME MEASURE: A clinically significant dose-response was defined as a rise in the post-ductal arterial oxygen tension (PaO(2)) of at least 3 kPa. RESULTS: Thirteen infants were recruited. At trial entry, ten were < 3 days of age; 11 were being treated with high frequency oscillatory ventilation; median (inter-quartile range) gestational age 27 (25-29) weeks; birthweight 983 (765-1120) g; oxygenation index 27.1 (21.8-28.8). Six infants (46%) showed a clinically significant response. After adjusting for period and patient effect, no evidence for an overall dose effect was identified (likelihood ratio test, p=0.34). CONCLUSION: No evidence of a dose-response relationship with iNO was found in this study of very preterm infants with respiratory failure.

The role of matrix metalloproteinases -9 and -2 in development of neonatal chronic lung disease.

AIM: Matrix metalloproteinases (MMPs) -9 and -2 degrade type-IV collagen, a major constituent of lung basement membrane, and may have a role in the pathogenesis of neonatal chronic lung disease (CLD). We determined factors influencing MMP levels in neonatal bronchoalveolar lavage (BAL) fluid to establish whether an imbalance between MMP and its inhibitor could be implicated in CLD. METHODS: We measured MMP-9 and -2 and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels in 316 BAL fluid samples from 121 babies of gestational ages 23 to 42 wk over the first 14 d of life to determine effects of gestation and postnatal age. Median MMP-9, -2, TIMP-1 and MMP-9/TIMP-1 ratio in BAL were further studied in a subgroup of 85 babies <33 wk gestation to determine their ability to predict CLD and to establish effects of antenatal corticosteroid therapy (ANCS). RESULTS: MMP-9, -2 and TIMP levels did not vary with postnatal age over the first week. Median MMP-9 levels and MMP-9/TIMP-1 ratio increased with decreasing gestation in preterm babies. The MMP-9/TIMP-1 ratio was higher in babies who developed CLD, implying a proteinase/antiproteinase imbalance, but this association disappeared when controlled for gestational age. ANCS had no effect on BAL fluid MMP or TIMP levels. CONCLUSION: MMPs may have a role in the development of lung injury and fibrosis, but estimating their levels in the first week of life does not help with prediction of CLD.

Chorioamnionitis increases matrix metalloproteinase-8 concentrations in bronchoalveolar lavage fluid from preterm babies.

OBJECTIVE: To determine the effects of chorioamnionitis and antenatal corticosteroids on matrix metalloproteinase-8 (MMP-8) concentrations in bronchoalveolar lavage (BAL) fluid from preterm babies in the first week of life. DESIGN: Prospective observational study. SETTING: Regional neonatal intensive care unit. PATIENTS: Thirty five ventilated preterm babies < 33 weeks gestation, seven of whom were born after chorioamnionitis, which was diagnosed histologically as the presence of inflammatory cells in the chorioamnionic plate. METHODS: MMP-8 was measured by enzyme linked immunosorbent assay (ELISA) in 90 serial BAL samples taken during the first six postnatal days. The median MMP-8 concentration for each baby was calculated. RESULTS: Median MMP-8 concentrations were higher in the chorioamnionitis group than in those without (43 v 5 ng/ml). Partial or complete courses of antenatal corticosteroids had no effect on MMP-8 concentrations. CONCLUSIONS: Higher concentrations of MMP-8 are found in BAL fluid from preterm babies from pregnancies complicated by chorioamnionitis. This type I collagenase may contribute to the lung injury that occurs in some babies with respiratory distress syndrome.

Oxidative stress in lavage fluid of preterm infants at risk of chronic lung disease.

There is evidence that oxidative stress plays a role in the development of chronic lung disease (CLD), with immature lungs being particularly sensitive to the injurious effect of oxygen and mechanical ventilation. We analyzed total ascorbate, urate, and protein carbonyls in 102 bronchoalveolar lavage fluid samples from 38 babies (33 preterm, 24-36 wk gestation; 5 term, 37-39 wk gestation). Preterm babies had significantly decreasing concentrations of ascorbate, urate, and protein carbonyls during the first 9 days of life (days 1-3, 4-6, and 7-9, Kruskal-Wallis ANOVA: P = 0.016, P < 0.0001, and P = 0.010, respectively). Preterm babies had significantly higher protein carbonyl concentrations at days 1-3 and 4-6 (P = 0.005 and P = 0.044) compared with term babies. Very preterm babies (24-28 wk gestation) had increased concentrations of protein carbonyls at days 4-6 (P = 0.056) and significantly decreased ascorbate concentrations at days 4-6 (P = 0.004) compared with preterm babies (29-36 wk gestation). Urate concentrations were significantly elevated at days 1-3 (P = 0.023) in preterm babies who subsequently developed CLD. This study has shown the presence of oxidative stress in the lungs of preterm babies during ventilation, especially in those who subsequently developed CLD.

Cord blood transferrin receptors to assess fetal iron status.

OBJECTIVE: To study iron status at different gestational ages using cord blood serum transferrin receptors (STfRs). METHODS: STfRs, iron, ferritin, total iron binding capacity, haemoglobin, and reticulocytes were measured in 144 cord blood samples. The babies were divided into three groups according to gestation (26 very preterm (24-29 weeks); 50 preterm (30-36 weeks); 68 term (37-41 weeks)). RESULTS: Serum iron, ferritin, and total iron binding capacity were highest at term, whereas reticulocytes were highest in the very preterm. STfR levels were not influenced by gestation. Haemoglobin (r = 0.46; p < 0.0001) and reticulocytes (r = 0.42; p < 0.0001) were the only indices that independently correlated with STfR levels. CONCLUSIONS: STfR levels in cord blood are not directly influenced by gestation and probably reflect the iron requirements of the fetus for erythropoiesis.

Oxidative stress and increased type-IV collagenase levels in bronchoalveolar lavage fluid from newborn babies.

Oxidative stress may increase lung permeability by up-regulation of matrix-metalloproteinase-9 (MMP-9), a type-IV collagenase that can disrupt alveolar basement membranes. We have compared a marker of oxidative stress (protein carbonyl residues) with levels of MMP-9 and its inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), in bronchoalveolar lavage samples from newborn babies. Bronchoalveolar lavage samples (n = 87, two from each time point) were taken in the first 6 postnatal days from 41 ventilated babies: 18 of <29 wk gestation, 10 of 29-36 wk, 9 term with persistent fetal circulation, and 4 term without lung disease. Respiratory disease severity at the time of bronchoalveolar lavage was assessed using the arterial-alveolar oxygen tension ratio. One sample from each time point was used for the measurement of MMP-9 by zymography and TIMP-1 by ELISA. The second sample was used to measure carbonyl group concentrations, also using an ELISA. Correlations were calculated between protein carbonyls, arterial-alveolar oxygen tension ratio, and MMP-9 and TIMP-1 concentrations. Significant correlations were found between carbonyl concentrations and arterial-alveolar oxygen tension ratio (r = -0.325, p = 0.0031, n = 81), MMP-9 (r = 0.331, p < 0.0029, n = 79), and TIMP-1 (r = 0.436, p < 0.0001, n = 87). Worsening respiratory disease in newborn babies is associated with increased carbonyl concentrations in neonatal bronchoalveolar lavage fluid, and these correlated with MMP-9 and TIMP-1 levels. Increased oxidative stress may damage the lung by increasing type-IV collagenase activity, causing disruption of the extracellular matrix.

Type I collagenases in bronchoalveolar lavage fluid from preterm babies at risk of developing chronic lung disease.

OBJECTIVE: To assess whether increased collagenolysis precedes severe chronic lung disease (CLD). METHODS: Matrix metalloproteinase-1 (MMP-1) and MMP-8 (enzymes that degrade type I collagen, the main structural protein of lung extracellular matrix) were measured by enzyme linked immunosorbent assay in 100 bronchoalveolar lavage samples taken during the first 6 postnatal days from 45 ventilated preterm babies < 33 weeks gestation. The median value for each baby was calculated. CLD was defined as an oxygen requirement after the 36th week after conception. RESULTS: MMP-8 levels in bronchoalveolar lavage fluid were higher (median 13 ng/ml) in 20 babies who developed CLD than in 25 without CLD (median 2 ng/ml). No MMP-1 was detected in any sample. CONCLUSIONS: MMP-8 can be detected in bronchoalveolar lavage fluid from preterm babies, and higher levels are found in those who later develop CLD. MMP-8 may contribute to lung injury that occurs as a prelude to CLD.

A trial of recombinant human granulocyte colony stimulating factor for the treatment of very low birthweight infants with presumed sepsis and neutropenia.

OBJECTIVES: The primary objective was to investigate the safety of recombinant human granulocyte colony stimulating factor (rhG-CSF) for the treatment of very low birthweight infants (VLBW) with sepsis and relative neutropenia, specifically with regard to worsening of respiratory distress and thrombocytopenia and all cause mortality. Secondary objectives were to evaluate duration of ventilation, intensive care, and antibiotic use as markers of efficacy. DESIGN: Neonates (< or = 28 days) in intensive care, with birth weights of 500-1500 g, absolute neutrophil count (ANC) of < or = 5 x 10(9)/l, and clinical evidence of sepsis, were randomly assigned to receive either rhG-CSF (10 microg/kg/day) administered intravenously (n = 13), or placebo (n = 15) for a maximum of 14 days, in addition to standard treatment and antibiotics. All adverse events, oxygenation index, incidence of thrombocytopenia, all cause mortality, duration of ventilation, intensive care and antibiotic treatment, and ANC recovery were compared between the two groups. RESULTS: Adverse events and oxygenation index were not increased by, and thrombocytopenia was not attributable to, treatment with rhG-CSF. At 6 and 12 months postmenstrual age, there were significantly fewer deaths in the group receiving rhG-CSF (1/13 v 7/15; p < or = 0.038). There was a non-significant trend towards a reduction in duration of ventilation, intensive care, and antibiotic use in the rhG-CSF group. There was a significantly more rapid increase in ANC in the rhG-CSF treated babies (p < 0.001). CONCLUSIONS: In a small randomised placebo controlled trial in a highly selected group of neonates, adjuvant treatment with rhG-CSF increased ANC rapidly, and no treatment related adverse events were identified. Mortality at 6 and 12 months postmenstrual age was significantly lower in the treatment group. A large trial investigating efficacy in a similar group of neonates is warranted.

Study of maternal influences on fetal iron status at term using cord blood transferrin receptors.

AIMS: To determine effects of maternal iron depletion and smoking on iron status of term babies using serum transferrin receptors (STfR) and their ratio to ferritin (TfR-F index) in cord blood. METHODS: Iron, ferritin, STfR, and haemoglobin (Hb) concentration were measured and TfR-F index calculated in 67 cord /maternal blood pairs. Twenty six mothers were iron depleted (ferritin <10 microg/l) and 28 were smokers. RESULTS: Maternal iron depletion was associated with decreased cord ferritin (113 v 171 microg/l) and Hb (156 v 168 g/l) but no change in STfR or TfR-F index. Smoking was associated with increased cord Hb (168 v 157 g/l) and TfR-F index (4.1 v 3.4), and decreased ferritin (123 v 190 microg/l). Cord TfR-F index and Hb were positively correlated (r = 0.48). CONCLUSIONS: Maternal iron depletion is associated with reduced fetal iron stores but no change in free iron availability. Smoking is associated with increased fetal iron requirements for erythropoiesis.

A risk-benefit assessment of drugs used for neonatal chronic lung disease.

Improvements in neonatal intensive care have resulted in more extremely low birthweight babies surviving who are at risk of developing chronic lung disease. The preterm lung is vulnerable as it is both structurally immature and deficient in surfactant and antioxidant defences. Mechanical ventilation and high inspired oxygen concentrations are often necessary for preterm babies to survive but they can cause pulmonary inflammation which leads to lung damage. Abnormal healing in the presence of ongoing inflammation leads to airways remodelling which can result in protracted respiratory problems in these babies. A commonly used definition for chronic lung disease is the requirement for supplemental oxygen beyond 36 weeks' postconception. Many drugs that are commonly used for chronic lung disease have not been subjected to proper randomised controlled trials but are widely used on the basis of small studies showing short term benefits. They can be broadly divided into 2 groups. First, there are preventative drugs that are administered early to reduce oxygen toxicity and pulmonary inflammation. Secondly, there are those administered in established chronic lung disease, designed to reduce respiratory morbidity. Pulmonary inflammation in the neonate is reduced by systemic corticosteroids. Corticosteroid therapy within the first 2 weeks of life enables earlier extubation of preterm babies with subsequent reduced chronic lung disease and improved neonatal survival when given between 7 and 14 days. However, there is an increased risk of gastrointestinal haemorrhage, metabolic derangement, ventricular hypertrophy and potential effects on long term growth and brain development. Diuretics and inhaled bronchodilators improve pulmonary compliance and reduce oxygen requirements in established chronic lung disease but probably have little effect in reducing the incidence. In babies with established chronic lung disease, home oxygen therapy enables earlier discharge and prophylaxis against respiratory syncytial virus can reduce morbidity from bronchiolitis. All of the above therapies have adverse effects that need to be considered before initiating treatment. Recently, new drugs have become available which may be beneficial. These include inhaled nitric oxide for reduction of ventilation-perfusion mismatching, recombinant human superoxide dismutase for protection against oxidative stress and alpha-1 proteinase inhibitor which may reduce airways remodelling. At present these therapies are undergoing clinical trials. Exogenous surfactant is beneficial in respiratory distress syndrome and may reduce the risk of chronic lung disease but there have been no randomised controlled trials of its use in established chronic lung disease. Drugs which have been tried unsuccessfully include erythromycin, ambroxol and mast cell stabilisers.

The effect of early feeding on the neonatal blood glucose level at 1-hour of age.

Early infant feeding after birth is being promoted, although it is unclear whether this has any effect on carbohydrate metabolism. We planned to measure the capillary glucose at one hour (1 h) of age in a group of infants from non-diabetic pregnancies using the HemoCue B-Glucose system to see if the timing and method of early feeding would influence this result. Seventy-five term infants were studied, 22 of which were breast-fed, 24 bottle fed and 29 not fed during the first hour after birth. The mean whole blood glucose results were 2.34 mmol/l, 2.52 mmol/l and 2.58 mmol/l respectively (P = NS). The first two groups were fed at a median of 22 minutes before sampling. We conclude that the timing and method of early feeding in the newborn have no significant effect on the blood glucose level measured at 1 h of age, and this remains a reliable outcome measure in studies of glucose metabolism in pregnancy.

Current perspectives on the drug treatment of neonatal respiratory distress syndrome.

Respiratory distress syndrome (RDS) in preterm neonates is caused by a lack of alveolar surfactant, which leads to decreased pulmonary compliance and increased work of breathing. Effective therapy for RDS has reduced mortality at the expense of increasing the number of preterm survivors with chronic lung disease. Drugs such as corticosteroids, proterelin (thyrotropin-releasing hormone) and ambroxol have all been administered to mothers to promote fetal lung maturation, but of these only corticosteroids have been proven to be of benefit. The management of RDS includes assisted ventilation and surfactant replacement therapy. There are several surfactant preparations, some synthetic and others derived from animal lungs, and recent research has been directed at finding which, if any, is superior. The timing of the first dose has also been studied. Prophylactic surfactant administration within the first 15 minutes of life appears to be more efficacious than later treatment for very preterm babies, but could lead to some neonates being treated unnecessarily and perhaps being exposed to adverse effects. Newer treatments for neonates with RDS are aimed at reducing the pulmonary inflammation that occurs as a result of ventilatory barotrauma and oxygen toxicity. Superoxide dismutase, along with other antioxidants, may be beneficial as a free radical scavenger to reduce oxygen toxicity. Inhaled nitric oxide may reduce oxygen requirements by reducing ventilation-perfusion mismatching, and early treatment with corticosteroids may reduce pulmonary inflammation. All of these treatments are currently undergoing clinical trials.

Comparison between creatine kinase brain isoenzyme (CKBB) activity and Sarnat score for prediction of adverse outcome following perinatal asphyxia.

AIM: To assess whether plasma creatine kinase brain isoenzyme (CKBB) levels or Sarnat scores are more accurate for prediction of poor neurological outcome in babies with suspected birth asphyxia. METHODS: In a retrospective study of 97 babies CKBB levels were compared to the presence of severe hypoxic ischaemic encephalopathy (HIE) as a predictive test for these outcomes: developmental delay, cerebral palsy, visual problems, deafness or death from perinatal asphyxia. The tests were compared using positive predictive values (PPV) and likelihood ratios (LR) with confidence intervals (CI). RESULTS: 3 babies had died from perinatal asphyxia and 14 survivors were found to have neurological or developmental problems. CKBB was elevated in babies with severe HIE (p = 0.0004). A receiver operator characteristic (ROC) curve showed the optimal discriminating value for CKBB to be 21 IU/L but the CKBB was a poor predictive test. For prediction of adverse outcome: CKBB > 21 sensitivity 76%, specificity 40%, PPV 21% and LR 1.3 (95% CI 0.8-1.7). Severe HIE sensitivity 53%, specificity 95%, PPV 69% and LR 10.6 (95% CI 3.8-29.2). CONCLUSION: CKBB is elevated following birth asphyxia but is a poor predictor of adverse neurological outcome.

Gastro-intestinal complications following neonatal cardiac catheterisation.

BACKGROUND: Infants with congenital cyanotic heart disease are at increased risk of developing necrotising enterocolitis (NEC). We examined a cohort of infants with congenital cyanotic heart disease in order to assess the role of cardiac catheterisation in the pathogenesis of NEC. METHODS: Sixty-five infants with congenital cyanotic heart disease were assessed in a retrospective study. The incidence of gastrointestinal complications was compared between infants who required cardiac catheterisation and those who did not. RESULTS: There were 38 infants who required cardiac catheterisation and 27 who did not. Both groups were similar for known risk factors for NEC. Eleven of the catheterised infants developed bloody stools versus 4 of the non-catheterised infants (OR 2.34; 95% CI 0.65-8.36). Five of the catheterised infants developed classical NEC versus none of the non-catheterised infants (OR 4.24; 95% CI 0.47-38.5). Four of the five infants who developed NEC did so during re-introduction of feeds following cardiac catheterisation. CONCLUSION: Infants with congenital cyanotic heart disease appear to be at a greater risk of gastrointestinal complications including necrotising enterocolitis in the days following cardiac catheterisation. We suggest a more cautious approach to feeding is required during this period.