Andrew J Lyon

Randomised trial of erythromycin on the development of chronic lung disease in preterm infants

AIMS To determine if erythromycin given from birth reduces the inflammatory response and the incidence and severity of chronic lung disease. METHODS Seventy five infants less than 30 weeks of gestation and ventilated from birth for lung disease were randomly assigned to receive erythromycin intravenously for 7 days or to no treatment. Ureaplasma urealyticum was detected in tracheal secretions by culture and polymerase chain reaction. Differential cell counts were obtained from bronchoalveolar lavage fluid collected daily for 5 days and concentrations of the cytokines interluekins IL-1β and IL-8, and tumour necrosis factor α (TNF-α) were measured. Chronic lung disease (CLD) was defined as oxygen dependency at 36 weeks of gestation. RESULTS Nine infants (13%) were positive forU urealyticum. The inflammatory cytokines in the lungs increased over the first 5 days of life in all babies, but no association was found between their concentrations and the development of CLD. Those treated with erythromycin showed no significant differences from the non- treated group in the differential cell counts or concentrations of the cytokines. The two groups had a similar incidence of CLD. Babies infected with U urealyticum did not have a more pronounced cytokine response than those without infection. Chorioamnionitis was associated with significantly higher concentrations of IL-1β and IL-8 on admission: these babies had less severe acute lung disease and developed significantly less CLD. CONCLUSIONS U urealyticum in the trachea was not associated with an increased inflammatory response in preterm infants. Erythromycin did not reduce the incidence or severity of CLD.

Chronic lung disease of prematurity. The role of intra-uterine infection

Abstract The clinical, radiological and pathological features of chronic lung disease have changed from those seen when the condition was first described. Most babies who now develop chronic lung disease have a birth weight below 1000 g and have only mild early respiratory disease, requiring minimal ventilation and low concentrations of inspired oxygen. The underlying pathophysiology of long-term lung damage appears to be a disturbance of the normal alveolar development which is continuing after birth, resulting in emphysematous like lungs with fewer and larger alveoli. Alveolarisation is affected by a number of insults including ventilation, oxygen, nutritional problems, steroids and both antenatal and post-natal infection. A final common pathway for many of these insults is persistence of an acute inflammatory response in the airways. There is good evidence that intra-uterine exposure to pro-inflammatory cytokines, as a consequence of ascending infection, induces both preterm labour and inflammation in the airways which triggers the lung injury sequence before birth. These cytokines have also been shown to have major effects on other organs in the body, in particular their association with brain damage and cerebral palsy. Treatment with antibiotics from birth has not been shown to affect the incidence or severity of chronic lung disease. Conclusion Intra-uterine infection is not only a common cause of preterm onset of labour but also a trigger to lung injury which significantly increases the risk of development of long-term respiratory disease in the newborn infant.

Temperature control in very low birthweight infants during first five days of life

AIM To determine ranges for skin temperatures in infants weighing under 1000 g in the first five days of life. METHOD Abdominal skin and foot temperatures were automatically collected each second, averaged over 1 minute and stored on computer. A computer program analysed the data in 83 babies weighing under 1000 g at birth over the first five days of life and expressed the temperatures as means and standard deviation. The temperature patterns seen in these babies were also visually analysed. The relation between an increasing abdominal skin-foot temperature difference and other signs of hypovolaemia was also studied. RESULTS These babies all had similar temperature patterns. Just after birth there was little ability to vasoconstrict in the presence of cold stress and the babies behaved more like poikilothermic animals. Vasomotor tone developed in the first three days, resulting in a stabilisation of the abdominal skin temperature to a mean of 36.90C and a widening of the central-peripheral temperature difference (Td) to a mean of 1.00 C. A Td of > 20 C was associated with other evidence of hypovolaemia for only 11% of the time. CONCLUSIONS Infants weighing under 1000 g have poor vasomotor control at birth and are at increased risk from cold stress. After the first two to three days of life, monitoring the central-peripheral temperature difference gives an early indication of cold stress.

Clinical Diagnosis of Pneumothorax Is Late: Use of Trend Data and Decision Support Might Allow Preclinical Detection

Pneumothorax in the newborn has a significant mortality and morbidity. Early diagnosis would be likely to improve the outlook. Forty-two consecutive cases of pneumothorax that developed after admission to a tertiary referral neonatal medical intensive care unit over 4 y from 1993 to 1996 were reviewed. The time of onset of the pneumothorax was determined by retrospective evaluation of the computerized trend of transcutaneous carbon dioxide (tcpCO2) and oxygen tensions. The timing of the occurrence in the notes and x-rays determined the time of clinical diagnosis noted at the time. The difference was the time the condition was undiagnosed. The overall mortality before discharge was 45% (19cases), four patients succumbing within 2 h. The median time (range) between onset of pneumothorax and clinical diagnosis was 127 min (45–660 min). In most cases, the endotracheal tube was aspirated and the transcutaneous blood gas sensor was repositioned, and in at least 40% of the cases, the baby was reintubated before the diagnosis was made. Reference centiles were constructed for level of tcpCO2 and slope of the trended tcpCO2 over various time intervals (in minutes) from 729 infants from 23 to 42 wk gestation who needed intensive care during the first 7 d of life from the same time period. The 5-min tcpCO2 trend slopes were compared in index and matched control infants. The presence of five consecutive and overlapping 5-min slopes greater than the 90th centile showed good discrimination for a pneumothorax (area under the receiver operating characteristic curve, 89%). We concluded that 1) the clinical diagnosis of pneumothorax was late, occurring when infants decompensate;2) trend monitoring of tcpCO2 might allow the diagnosis to be made earlier if used properly; and 3) use of reference centiles of the trended slopes of tcpCO2 might be used for automatic decision support in the future.

Unexpected collapse in apparently healthy newborns--a prospective national study of a missing cohort of neonatal deaths and near-death events.

Background Sudden and unexpected postnatal collapse (SUPC) of a healthy newborn infant is a rare event, which carries a high risk of mortality and significant neurodisability in survivors. An underlying condition can be found in 60% of cases who undergo detailed postmortem but in the remainder there are important associations with prone position, breast feeding and primiparous status. The authors undertook a prospective study to ascertain the population incidence of SUPC in the UK. Methods Cases were referred through the British Paediatric Surveillance Unit reporting scheme over a 13-month period. Infants were at ≥37 weeks of gestation, had an Apgar score of ≥8 at 5 min, collapsed within 12 h in hospital requiring positive pressure ventilation and either died or received ongoing intensive care. Data were collected on maternal and infant characteristics, clinical investigations and 1-year outcome. Findings 45 cases were reported, an incidence of 0.05/1000 live births of whom 12 infants died. In 15/45 infants, an underlying disease/abnormality was determined. In 30/45 cases (0.035/1000 live births), no such cause was found, but in 24, the clinical/pathological diagnosis was airway obstruction during breast feeding or in prone position. Mothers were commonly primiparous and unattended by clinical staff before collapse was recognised. Approach to investigation was highly disparate and frequently very limited. Of the 30 infants with no underlying disease/abnormality, 22 (73%) developed a postasphyxial encephalopathy and 10 had a poor outcome (33%) – 5 died and 5 had neurological sequelae at 1 year. Interpretation SUPC is rare in any one centre and there is no standard approach to investigation. In those cases where collapse is not due to an underlying abnormality, breast feeding and prone position are important associations. Guidelines for safe postnatal care of infants should include appropriate vigilance of infants particularly where mothers are primiparous or where ability to assess the baby may be impaired.

Bone and collagen markers in preterm infants: relationship with growth and bone mineral content over the first 10 weeks of life.

In a longitudinal study of 25 preterm infants, we have examined the relationship of bone-specific alkaline phosphatase (ALP), C-terminal propeptide of type I collagen (PICP), N-terminal propeptide of type III procollagen (P3NP), C-terminal telopeptide of type I collagen, urinary pyridinoline (Pyd) and deoxypyridinoline (Dpd), with rates of gain in weight, length, and lower leg length and with bone mineral content (BMC), all measured at weekly intervals over the first 10 wk of life. Concentrations of all collagen markers were 10-fold higher than in older children. Each marker showed a distinctive pattern of postnatal change, with early increases in PICP and P3NP and decreases in ICTP reflecting postnatal growth. Once markers had reached a plateau during weeks 4–10, P3NP was positively correlated, whereas Pyd and Dpd were negatively correlated with rate of weight gain (r= +0.44, −0.46, and −0.40, respectively, p< 0.05). P3NP was also positively correlated with overall linear growth (r= +0.44, p< 0.05). PICP was strongly correlated with mean BMC (r= +0.63, p< 0.01) and with total BMC attained by the end of the study period (r= +0.81, p< 0.001). Bone ALP was positively correlated with the rate of bone mineral accretion (r= +0.55, p= 0.01). We conclude that the marker of soft-tissue collagen formation, P3NP, is a good marker for overall ponderal and linear growth in preterm infants, whereas the markers of collagen breakdown, Pyd and Dpd, have inverse relationships with weight gain. The osteoblast markers, PICP and bone ALP, seem to be good surrogate markers for bone mineralization in preterm infants. Markers may provide information on whole-body turnover of bone and collagen that is complementary to traditional physical measures of growth and bone mineralization.

Influence of erythromycin on establishment of feeding in preterm infants: observations from a randomised controlled trial.

AIM To determine the effect of erythromycin on the establishment of enteral feeding in ventilated infants <31 weeks gestation. METHODS Erythromycin was randomly allocated as an antimicrobial treatment for the first 7 days of life in 76 infants: 35 received erythromycin and 41 acted as controls. Feed toleration, time taken to establish full enteral feeding, vomiting, prescription of glycerine suppositories and occurrence of necrotising enterocolitis were recorded. RESULTS There were no significant differences between the groups for any of the outcomes. The infants treated with erythromycin reached full feeding at a median (quartile) age of 8 (5–12) days compared with 9 (6–14) days for controls. CONCLUSIONS Intravenous erythromycin in antimicrobial doses is unlikely to benefit the introduction of feeding in preterm infants.

Effects of Dexamethasone Treatment on Bone and Collagen Turnover in Preterm Infants with Chronic Lung Disease

Dexamethasone is used commonly in the treatment of chronic lung disease of prematurity, but there are concerns about possible deleterious effects on growth and bone. Our aim in this study was to examine the effects of dexamethasone treatment on bone and collagen turnover in preterm infants. Bone-specific alkaline phosphatase, the C-terminal propeptide of type I collagen (PICP, reflecting whole-body type I collagen synthesis), and the N-terminal propeptide of type III procollagen (P3NP, reflecting soft tissue collagen turnover), together with the C-terminal telopeptide of type I collagen (ICTP), urinary pyridinoline (Pyd), and deoxypyridinoline (all markers of collagen breakdown) were measured at weekly intervals over the first 12 wk of life in 14 preterm infants with chronic lung disease treated with dexamethasone. Results were expressed as SD scores relative to preterm control infants not treated with dexamethasone. PICP, P3NP, ICTP, and Pyd all showed marked decreases (−2.1 to −3.7 SD scores) during the first week of treatment (p < 0.001), returning to pretreatment levels after stopping dexamethasone. In the group as a whole, these collagen markers were negatively correlated with dexamethasone dose (p < 0.0001); negative correlations were also seen in most individual babies, although the slopes of individual regression lines varied by a factor of 2. Weight gain at 12 wk was correlated with PICP, expressed as the mean SD score over 12 wk for each baby, (r = 0.69, p < 0.01) but not with other markers or cumulative dose of dexamethasone. We conclude that dexamethasone markedly suppressed collagen turnover in preterm infants in a dose-dependent fashion, although some babies were more affected than others. The degree of suppression of type I collagen synthesis was a strong independent predictor of overall weight gain over the first 12 wk of life.

Who is blaming the baby

FIGURE 6. TRAILshort is both necessary and sufficient to cause TRAIL resistance. (A) Jurkat T cells, which constitutively express TRAILshort, were induced to die by the addition of sk-TRAIL, in the presence or absence of increasing amounts of anti-TRAILshort Ab. Cell death was measured by active caspase-3 staining. Control cells were treated with increasing anti-TRAILshort Ab alone. (B) HeLa cells, which do not express TRAILshort, were stimulated to die by the addition of sk-TRAIL in the absence or presence of increasing amounts of a fusion protein consisting of the extracellular domain of TRAILshort fused to Fc (TRAILshort-ECD:Fc) or with BSA control and analyzed as in (A). Additional control cells were treated with increasing TRAILshort-ECD:Fc alone. Data are representative of six independent experiments. p , 0.05 considered statistically significant (linear regression).Sudden unexplained collapse within the first 12 h of life is a rare but recognised event. Over a 2-year period, five infants, previously assessed as healthy, were found collapsed in our maternity unit in the care of their primiparous mothers. Two were found prone on their mother’s chest, and two were in their mother’s bed. The outcomes were poor, with four neonatal deaths and one death at 18 months. The rate of sudden unexplained neonatal collapse was 0.4 per 1000 live births. No cause for collapse was identified despite extensive investigations, which included postmortem in all the neonatal deaths. One infant, however, showed widespread antenatal brain damage at postmortem. It is postulated that some infants with an underlying vulnerability may maladapt to extrauterine life following an hypoxic stressor possibly caused by positional airway obstruction.

Biochemical Markers of Bone Turnover

Three studies to evaluate procollagen type I C-terminal propeptide, type I collagen cross-linked telopeptide and bone alkaline phosphatase (BALP) in the assessment of bone turnover and growth in children are presented. (1) In 50 short normal children treated with placebo or growth hormone, delta BALP after 3 months of treatment was highly correlated with height velocity response after 1 year (r = 0.67, p < 0.0001). (2) In 12 children with acute lymphoblastic leukaemia, marked changes in collagen peptides, BALP, and lower leg length velocity were seen during the first 6 months of chemotherapy. Suppression occurred during induction and the two intensification phases, with catch-up during the intervening phase (paired t-tests, p < 0.001). (3) Fourteen babies (birthweight < 1,500 g) treated with high-dose dexamethasone for bronchopulmonary dysplasia were compared with 25 non-steroid-treated babies < 1,500 g. Both collagen peptides decreased rapidly and dramatically (mean decreases 41-68%) after dexamethasone was started, accompanied by weight loss and lower leg shrinkage and followed by recovery during steroid weaning.