Sven M. Schulzke

A systematic review of cooling for neuroprotection in neonates with hypoxic ischemic encephalopathy – are we there yet?

BackgroundThe objective of this study was to systematically review randomized trials assessing therapeutic hypothermia as a treatment for term neonates with hypoxic ischemic encephalopathy.MethodsThe Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL databases, reference lists of identified studies, and proceedings of the Pediatric Academic Societies were searched in July 2006. Randomized trials assessing the effect of therapeutic hypothermia by either selective head cooling or whole body cooling in term neonates were eligible for inclusion in the meta-analysis. The primary outcome was death or neurodevelopmental disability at ≥ 18 months.ResultsFive trials involving 552 neonates were included in the analysis. Cooling techniques and the definition and severity of neurodevelopmental disability differed between studies. Overall, there is evidence of a significant effect of therapeutic hypothermia on the primary composite outcome of death or disability (RR: 0.78, 95% CI: 0.66, 0.92, NNT: 8, 95% CI: 5, 20) as well as on the single outcomes of mortality (RR: 0.75, 95% CI: 0.59, 0.96) and neurodevelopmental disability at 18 to 22 months (RR: 0.72, 95% CI: 0.53, 0.98). Adverse effects include benign sinus bradycardia (RR: 7.42, 95% CI: 2.52, 21.87) and thrombocytopenia (RR: 1.47, 95% CI: 1.07, 2.03, NNH: 8) without deleterious consequences.ConclusionIn general, therapeutic hypothermia seems to have a beneficial effect on the outcome of term neonates with moderate to severe hypoxic ischemic encephalopathy. Despite the methodological differences between trials, wide confidence intervals, and the lack of follow-up data beyond the second year of life, the consistency of the results is encouraging. Further research is necessary to minimize the uncertainty regarding efficacy and safety of any specific technique of cooling for any specific population.

Air Trapping on Chest CT Is Associated with Worse Ventilation Distribution in Infants with Cystic Fibrosis Diagnosed following Newborn Screening

Background In school-aged children with cystic fibrosis (CF) structural lung damage assessed using chest CT is associated with abnormal ventilation distribution. The primary objective of this analysis was to determine the relationships between ventilation distribution outcomes and the presence and extent of structural damage as assessed by chest CT in infants and young children with CF. Methods Data of infants and young children with CF diagnosed following newborn screening consecutively reviewed between August 2005 and December 2009 were analysed. Ventilation distribution (lung clearance index and the first and second moment ratios [LCI, M1/M0 and M2/M0, respectively]), chest CT and airway pathology from bronchoalveolar lavage were determined at diagnosis and then annually. The chest CT scans were evaluated for the presence or absence of bronchiectasis and air trapping. Results Matched lung function, chest CT and pathology outcomes were available in 49 infants (31 male) with bronchiectasis and air trapping present in 13 (27%) and 24 (49%) infants, respectively. The presence of bronchiectasis or air trapping was associated with increased M2/M0 but not LCI or M1/M0. There was a weak, but statistically significant association between the extent of air trapping and all ventilation distribution outcomes. Conclusion These findings suggest that in early CF lung disease there are weak associations between ventilation distribution and lung damage from chest CT. These finding are in contrast to those reported in older children. These findings suggest that assessments of LCI could not be used to replace a chest CT scan for the assessment of structural lung disease in the first two years of life. Further research in which both MBW and chest CT outcomes are obtained is required to assess the role of ventilation distribution in tracking the progression of lung damage in infants with CF.

Incidence and diagnosis of unilateral arterial cerebral infarction in newborn infants.

Abstract Aims: Magnetic resonance imaging (MRI) is accepted as the gold standard for the diagnosis of arterial cerebral infarction (ACI), but few studies have reported the incidence of neonatal ACI based on MRI findings. We provide new population-based epidemiologic and diagnostic data on all infants diagnosed between 1997 and 2002 in our center with an MRI-confirmed diagnosis of unilateral neonatal ACI. Results: Nine patients were identified, giving an incidence of 1:2300 unilateral ACIs in our inborn population. In all patients the middle cerebral artery was affected. Seven patients showed epileptic seizures, usually starting within the first 3 days of life. EEG was pathologic in all patients. Only three infarctions were diagnosed by ultrasound. Initial MRI established diagnosis of ACI in eight out of nine patients and subsequent MRI described the exact location of infarctions in all patients. Six out of nine patients developed hemiparesis and five had deficits in language development. There is a substantial need for special care facilities and long-term therapeutic interventions. Conclusions: The incidence of neonatal ACI is higher than previously reported. The sensitivity of early cerebral ultrasound for diagnosis of ACI is low. Seizures in the first 3 days of life combined with pathologic EEG findings should lead to MRI, regardless of normal cerebral ultrasound.

Oral ibuprofen versus intravenous ibuprofen or intravenous indomethacin for the treatment of patent ductus arteriosus in preterm infants: a systematic review and meta-analysis.

Background: Pharmacological closure of patent ductus arteriosus (PDA) is commonly achieved by intravenous (IV) administration of ibuprofen or indomethacin. Occasionally, oral ibuprofen is used for PDA treatment although its efficacy and safety are unclear. Objectives: To systematically review randomized and quasi-randomized trials comparing oral ibuprofen with IV ibuprofen or IV indomethacin for closure of PDA in preterm infants. Methods: The standard search methods of the Cochrane Neonatal Review Group were used. Results: We identified two studies (n = 166) of good methodological quality comparing oral ibuprofen with IV ibuprofen and three small trials (n = 92) of moderate methodological quality comparing oral ibuprofen to IV indomethacin. Meta-analysis showed higher PDA closure rate of oral ibuprofen versus IV ibuprofen but no difference between oral ibuprofen and IV indomethacin. Meta-analysis did not indicate a significant difference in adverse effects. Conclusion: Oral ibuprofen for PDA closure appears to be as effective as IV ibuprofen and IV indomethacin. Due to small sample size, lack of data in extremely preterm neonates, and methodological limitations of reviewed trials, definitive conclusions cannot be drawn. Randomized trials with a low risk of bias and adequate sample size in extremely preterm infants are urgently needed.

Pentoxifylline in preterm neonates: a systematic review.

Sepsis, necrotizing enterocolitis (NEC), and chronic lung disease (CLD) in preterm neonates are associated with significant mortality and morbidity, including long-term neurodevelopmental impairment and socioeconomic burden. Safe and effective drugs for the prevention and treatment of these conditions are urgently needed.Pentoxifylline, a synthetic theobromine derivative, is a non-steroidal immunomodulating agent with unique hemorrheologic effects which has been used in a range of infectious, vascular, and inflammatory conditions in adults and children. The unique properties of pentoxifylline explain its potential benefits in preterm neonates with sepsis, NEC, and CLD, conditions characterized by activation of the inflammatory cytokine cascade, free radical toxicity, and impaired microcirculation. Pentoxifylline has anti-inflammatory properties resulting from inhibition of erythrocyte phosphodiesterase. It lowers blood viscosity and improves microcirculation and tissue perfusion. As a phosphodiesterase inhibitor, pentoxifylline down-regulates pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and interferon-γ. Methylxanthines, including caffeine, theophylline, and theobromine are relatively non-toxic drugs; of these, theobromine is the least toxic. Pentoxifylline-related significant adverse events are thus very rare. Unlike other methylxanthines, pentoxifylline does not have significant cardiac and bronchodilating effects at therapeutic doses. Although it is contraindicated in adults with recent cerebral hemorrhage due to its effect on platelets, red blood cells, and plasma fibrinogen levels, no significant adverse effects including thrombocytopenia and bleeding have been reported in critically ill preterm neonates with sepsis or NEC after treatment with pentoxifylline.Based on data from pilot randomized trials and observational studies, our systematic review suggests that pentoxifylline may reduce mortality and/or morbidity in preterm neonates with sepsis, NEC, and CLD. Results of experimental studies also indicate that pentoxifylline may potentially be beneficial in meconium aspiration syndrome and hypoxic ischemic encephalopathy.Given the substantial burden of sepsis, NEC, and CLD in high-risk preterm neonates, and the findings of this systematic review, pentoxifylline needs to be evaluated urgently as a preventative and therapeutic agent for these conditions in randomized controlled trials that can detect minimal clinically significant effect sizes. Further clinical and experimental studies are also necessary to evaluate whether pentoxifylline is safe and effective in meconium aspiration syndrome and hypoxic ischemic encephalopathy.

Lung Volume and Ventilation Inhomogeneity in Preterm Infants at 15-18 Months Corrected Age

OBJECTIVE To assess whether lung volume and ventilation inhomogeneity in preterm infants at 15-18 months corrected age, and the change in these outcomes from the newborn period to 15-18 months corrected age, depend on gestational age (GA) at birth and the severity of neonatal lung disease. STUDY DESIGN Preterm (GA range, 23-32 weeks) and term healthy control infants were studied in quiet sedated sleep at 15-18 months corrected age by multiple breath washout with 5% sulfur hexafluoride using an ultrasonic flowmeter. Valid measurements were obtained from 58 infants. Multivariate and multilevel regression was used to analyze outcomes. RESULTS Functional residual capacity (FRC), lung clearance index, and first and second to zeroeth moment ratios were calculated. After accounting for body size at test, FRC at follow-up, and the increase in FRC from the newborn period to 15-18 months corrected age were positively associated with GA and negatively associated with the duration of endotracheal ventilation. Indices of ventilation inhomogeneity were unaltered by GA and the duration of endotracheal ventilation. CONCLUSIONS In very preterm infants, GA and the duration of endotracheal ventilation are independently associated with reduced lung volume and lung growth during infancy, although the effect size of these findings is small.

Safety of Early High-Dose Recombinant Erythropoietin for Neuroprotection in Very Preterm Infants.

OBJECTIVE To investigate the safety and short term outcome of high dose recombinant human erythropoietin (rhEpo) given shortly after birth and subsequently over the first 2 days for neuroprotection to very preterm infants. STUDY DESIGN Randomized, double masked phase II trial. Preterm infants (gestational age 26 0/7-31 6/7 weeks) were given rhEpo (nt = 229; 3000 U/kg body weight) or NaCl 0.9% (nc = 214) intravenously at 3, 12-18, and 36-42 hours after birth. RESULTS There were no relevant differences between the groups for short-term outcomes such as mortality, retinopathy of prematurity, intraventricular hemorrhage, sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia. At day 7-10, we found significantly higher hematocrit values, reticulocyte, and white blood cell counts, and a lower platelet count in the rhEpo group. CONCLUSIONS Early high-dose rhEpo administration to very premature infants is safe and causes no excess in mortality or major adverse events. TRIAL REGISTRATION ClinicalTrials.gov: NCT00413946.

The management of evolving bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is associated with increased mortality and significant long-term cardiorespiratory and neurodevelopmental sequelae. Treatment of evolving BPD in the neonatal intensive care unit (NICU) is challenging due to the complex interplay of contributing risk factors which include preterm birth per se, supplemental oxygen, positive pressure ventilation, patent ductus arterious, and pre- and postnatal infection. Management of evolving BPD requires a multimodal approach including adequate nutrition, careful fluid management, effective and safe pharmacotherapy, and respiratory support aiming at minimal lung injury. Among pharmacological interventions, caffeine has the best risk-benefit profile. Systemic postnatal corticosteroids should be reserved to ventilated infants at highest risk of BPD who cannot be weaned from the ventilator. Several ongoing randomised trials are evaluating optimal oxygen saturation targets in preterm infants. The most beneficial respiratory support strategy to minimise lung injury remains unclear and requires further investigation.

Volumetric Capnography in Infants with Bronchopulmonary Dysplasia

OBJECTIVES To assess the feasibility of using volumetric capnography in spontaneously breathing small infants and its ability to discriminate between infants with and without bronchopulmonary dysplasia (BPD). STUDY DESIGN Lung function variables for 231 infants (102 term, 52 healthy preterm, 77 BPD), matched for post-conceptional age of 44 weeks, were collected. BPD was defined as supplemental oxygen requirement at 36 weeks post-menstrual age. Tidal breath-by-breath volume capnograms were obtained by mainstream capnography. The capnographic slope of phase II (SII) and slope of phase III (SIII) were calculated and compared between study groups. The effect of BPD, tidal volume (VT), respiratory rate (RR), and prematurity on the magnitude of the slopes was assessed. RESULTS SII was steeper in infants with BPD (100 ± 28/L) compared with healthy preterm (88 ± 22/L; P = .007) and term infants (79 ± 18/L; P < .001), but this finding was attributed to differences in VT, RR, and gestational age. SIII was steeper in the BPD group (26.8 ± 14.1/L) compared with healthy preterm (16.2 ± 6.2/L; P < .001) and term controls (14.8 ± 5.4/L; P < .001). BPD was a significant predictor of SIII independently of VT, RR, and gestational age. The ability of SIII to discriminate between BPD and controls was significantly higher compared with lung clearance index (area under the curve 0.83 vs 0.56; P < .001). CONCLUSIONS Volumetric capnography may provide valuable information regarding functional lung alterations related to BPD and might be considered as an alternative to more involved lung function techniques for monitoring chronic lung disease during early infancy.

The predictive value of quantitative fibronectin testing in combination with cervical length measurement in symptomatic women

BACKGROUND The combination of the qualitative fetal fibronectin test and cervical length measurement has a high negative predictive value for preterm birth within 7 days; however, positive prediction is poor. A new bedside quantitative fetal fibronectin test showed potential additional value over the conventional qualitative test, but there is limited evidence on the combination with cervical length measurement. OBJECTIVE The purpose of this study was to compare quantitative fetal fibronectin and qualitative fetal fibronectin testing in the prediction of spontaneous preterm birth within 7 days in symptomatic women who undergo cervical length measurement. STUDY DESIGN We performed a European multicenter cohort study in 10 perinatal centers in 5 countries. Women between 24 and 34 weeks of gestation with signs of active labor and intact membranes underwent quantitative fibronectin testing and cervical length measurement. We assessed the risk of preterm birth within 7 days in predefined strata based on fibronectin concentration and cervical length. RESULTS Of 455 women who were included in the study, 48 women (11%) delivered within 7 days. A combination of cervical length and qualitative fibronectin resulted in the identification of 246 women who were at low risk: 164 women with a cervix between 15 and 30 mm and a negative fibronectin test (<50 ng/mL; preterm birth rate, 2%) and 82 women with a cervix at >30 mm (preterm birth rate, 2%). Use of quantitative fibronectin alone resulted in a predicted risk of preterm birth within 7 days that ranged from 2% in the group with the lowest fibronectin level (<10 ng/mL) to 38% in the group with the highest fibronectin level (>500 ng/mL), with similar accuracy as that of the combination of cervical length and qualitative fibronectin. Combining cervical length and quantitative fibronectin resulted in the identification of an additional 19 women at low risk (preterm birth rate, 5%), using a threshold of 10 ng/mL in women with a cervix at <15 mm, and 6 women at high risk (preterm birth rate, 33%) using a threshold of >500 ng/mL in women with a cervix at >30 mm. CONCLUSION In women with threatened preterm birth, quantitative fibronectin testing alone performs equal to the combination of cervical length and qualitative fibronectin. Possibly, the combination of quantitative fibronectin testing and cervical length increases this predictive capacity. Cost-effectiveness analysis and the availability of these tests in a local setting should determine the final choice.