Neurally adjusted ventilatory assist in preterm infants: A systematic review and meta-analysis.

To compare the effects of neurally adjusted ventilatory assist (NAVA) with other forms of synchronized artificial ventilation in preterm infants. A systematic review of randomized and quasi-randomized controlled trials with individual group allocation, both parallel-group trials as well as crossover trials, that included preterm infants born at less than 37 weeks gestational age and compared NAVA with any other form of synchronized mechanical ventilation with or without volume guarantee. Primary outcomes were death or bronchopulmonary dysplasia (BPD) at 36 weeks, total duration of respiratory support and neurodevelopmental outcome at 2 years. Secondary outcomes consisted of important procedural and clinical outcomes. Seven studies with a total of 191 infants were included, five randomized crossover trials and two parallel group randomized trials. No significant difference in the primary outcome of death or BPD (RR: 1.08, 95% CI: 0.33-3.55) was found. Peak inspiratory pressures were significantly lower with NAVA than with other forms of ventilation (MD -1.83 cmH2O [95% CI: -2.95 to -0.71]). No difference in any other clinical or ventilatory outcome was detected. Although associated with lower peak inspiratory pressures, the use of NAVA does not result in a reduced risk of death or BPD as compared to other forms of synchronized ventilation in preterm infants. However, the certainty of evidence is low due to imprecision of the effect estimate. Larger studies are needed to detect possible short- and long-term differences between ventilation modes.

Effect of Systemic Hydrocortisone on Brain Abnormalities and Regional Brain Volumes in Ventilator-dependent Infants Born Preterm: Substudy of the SToP-BPD Study.

OBJECTIVE: To evaluate whether a high cumulative dose of systemic hydrocortisone affects brain development compared with placebo when initiated between 7 and 14 days after birth in ventilated infants born preterm. STUDY DESIGN: A double-blind, placebo-controlled, randomized trial was conducted in 16 neonatal intensive care units among infants born at <30 weeks of gestation or with a birth weight of <1250 g who were ventilator-dependent in the second week after birth. Three centers performed MRI at term-equivalent age. Brain injury was assessed on MRI using the Kidokoro scoring system and compared between the 2 treatment groups. Both total and regional brain volumes were calculated using an automatic segmentation method and compared using multivariable regression analysis adjusted for baseline variables. RESULTS: From the 3 centers, 78 infants participated in the study and 59 had acceptable MRI scans (hydrocortisone group, n = 31; placebo group, n = 28). Analyses of the median global brain abnormality score of the Kidokoro score showed no difference between the hydrocortisone and placebo groups (median, 7; IQR, 5-9 vs median, 8, IQR, 4-10, respectively; P = .92). In 39 infants, brain tissue volumes were measured, showing no differences in the adjusted mean total brain tissue volumes, at 352 ± 32 mL in the hydrocortisone group and 364 ± 51 mL in the placebo group (P = .80). CONCLUSIONS: Systemic hydrocortisone started in the second week after birth in ventilator-dependent infants born very preterm was not found to be associated with significant differences in brain development compared with placebo treatment. TRIAL REGISTRATION: The SToP-BPD study was registered with the Netherlands Trial Register (NTR2768; registered on 17 February 2011; https://www.trialregister.nl/trial/2640) and the European Union Clinical Trials Register (EudraCT, 2010-023777-19; registered on 2 November 2010; https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-023777-19/NL).

Effect of systemic hydrocortisone in ventilated preterm infants on parent-reported behavioural outcomes at 2 years' corrected age: follow-up of a randomised clinical trial.

OBJECTIVE: To report the parent-reported behavioural outcomes of infants included in the Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants study at 2 years' corrected age (CA). DESIGN: Randomised placebo-controlled trial. SETTING: Dutch and Belgian neonatal intensive care units. PATIENTS: Infants born <30 weeks' gestation and/or birth weight <1250 g, and ventilator dependent in the second week of life. INTERVENTION: Infants were randomly assigned to a 22-day course of systemic hydrocortisone (cumulative dose 72.5 mg/kg; n=182) or placebo (n=190). MAIN OUTCOME MEASURES: Parent-reported behavioural outcomes at 2 years' CA assessed with the Child Behavior Checklist (CBCL 1½-5). RESULTS: Parents completed the CBCL of 183 (70% (183/262)) infants (hydrocortisone group, n=96; placebo group, n=87). Multiple imputation was used to account for missing data. Infants with critically elevated T-scores (>55) were found in 22.9%, 19.1% and 29.4% of infants for total, internalising and externalising problems, respectively; these scores were not significantly different between groups (mean difference -1.52 (95% CI -4.00 to 0.96), -2.40 (95% CI -4.99 to 0.20) and -0.81 (95% CI -3.40 to 1.77), respectively). In the subscales, we found a significantly lower T-score for anxiety problems in the hydrocortisone group (mean difference -1.26, 95% CI -2.41 to -0.12). CONCLUSION: This study found high rates of behaviour problems at 2 years' CA following very preterm birth, but these problems were not associated with hydrocortisone treatment initiated between 7 and 14 days after birth in ventilated preterm infants. TRIAL REGISTRATION NUMBER: NTR2768; EudraCT 2010-023777-19.

Continuous Deep Sedation until Death in Neonates and Infants in Flanders: A Post-Mortem Survey.

BACKGROUND: The use of analgesics and sedatives to alleviate pain and discomfort is common in end-of-life care in neonates and infants. However, to what extent those drugs are used in that context with the specific aim of bringing the infant in a state of continuous deep sedation (CDS) is currently unknown. METHODS: We performed a nationwide mortality follow-back survey based on all deaths under the age of 1 over a period of 16 months in Flanders, Belgium. Data on CDS were linked to sociodemographic information from death certificates. Physicians completed an anonymous questionnaire. Questions measured whether CDS preceded death, and which clinical characteristics were associated with the sedation (e.g., type of drugs used and the duration of sedation). RESULTS: The response rate was 83% (229/276). In 39% of all deceased neonates and infants, death was preceded by CDS. Physicians used a combination of morphine and benzodiazepines in 53%, or morphine alone in 45% of all sedation cases in order to continuously and deeply sedate the infant. In 89% of cases, death occurred within 1 week after sedation was begun, and in 92% of cases, artificial nutrition and hydration were administered until death. In 49% of cases there was no intention to hasten death, and in 40% of cases, the possibility of hastening was taken into account. CONCLUSIONS: CDS precedes about 2 in 5 neonatal and infant deaths. Guidelines for CDS in this age group are non-existent and it is unclear whether the same recommendations as in the adult population apply and can be considered a good practice.

Neuropathology of genetically defined malformations of cortical development-A systematic literature review.

AIMS: Malformations of cortical development (MCD) include a heterogeneous spectrum of clinical, imaging, molecular and histopathological entities. While the understanding of genetic causes of MCD has improved with the availability of next-generation sequencing modalities, genotype-histopathological correlations remain limited. This is the first systematic review of molecular and neuropathological findings in patients with MCD to provide a comprehensive overview of the literature. METHODS: A systematic review was performed between November 2019 and February 2020. A MEDLINE search was conducted for 132 genes previously linked to MCD in order to identify studies reporting macroscopic and/or microscopic findings in patients with a confirmed genetic cause. RESULTS: Eighty-one studies were included in this review reporting neuropathological features associated with pathogenic variants in 46 genes (46/132 genes, 34.8%). Four groups emerged, consisting of (1) 13 genes with well-defined histological-genotype correlations, (2) 27 genes for which neuropathological reports were limited, (3) 5 genes with conflicting neuropathological features, and (4) 87 genes for which no histological data were available. Lissencephaly and polymicrogyria were reported most frequently. Associated brain malformations were variably present, with abnormalities of the corpus callosum as most common associated feature. CONCLUSIONS: Neuropathological data in patients with MCD with a defined genetic cause are available only for a small number of genes. As each genetic cause might lead to unique histopathological features of MCD, standardised thorough neuropathological assessment and reporting should be encouraged. Histological features can help improve the understanding of the pathogenesis of MCD and generate hypotheses with impact on further research directions.

A Systematic Review and Meta-Analysis of Endocrine-Related Adverse Events Associated with Immune Checkpoint Inhibitors.

Monoclonal antibodies targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4), programed cell death 1 (PD-1), or its ligand (PD-L1) have become the mainstay for advanced malignancies. The incidence of endocrine adverse events provoked by these immune checkpoint inhibitors (ICI) is based on data from randomized controlled trials, which have their drawbacks. PubMed was searched through August 22nd, 2017, by 2 reviewers independently (J.d.F. and C.E.A.). Early phase I/II, phase III experimental trials, prospective and retrospective observational studies were included. The weighted incidence and risk ratio were estimated for hypophysitis, primary thyroid disease, primary adrenal insufficiency, and diabetes mellitus. Their management is discussed in a systematic review. A total of 101 studies involving 19 922 patients were included. Ipilimumab-treated patients experienced hypophysitis in 5.6% (95% CI, 3.9-8.1), which was higher than nivolumab (0.5%; 95% CI, 0.2-1.2) and pembrolizumab (1.1%; 95% CI, 0.5-2.6). PD-1/PD-L1 inhibitors had a higher incidence of thyroid dysfunction - particularly hypothyroidism (nivolumab, 8.0%; 95% CI, 6.4-9.8; pembrolizumab, 8.5%; 95% CI, 7.5-9.7; PD-L1, 5.5%; 95% CI, 4.4-6.8; ipilimumab, 3.8%; 95% CI, 2.6-5.5). Combination therapy was associated with a high incidence of hypothyroidism (10.2-16.4%), hyperthyroidism (9.4-10.4%), hypophysitis (8.8-10.5%), and primary adrenal insufficiency (5.2-7.6%). Diabetes mellitus and primary adrenal insufficiency were less frequent findings on monotherapy. Our meta-analysis shows a high incidence of endocrine adverse events provoked by single agent checkpoint blockade, further reinforced by combined treatment.

Effect of Hydrocortisone Therapy Initiated 7 to 14 Days After Birth on Mortality or Bronchopulmonary Dysplasia Among Very Preterm Infants Receiving Mechanical Ventilation: A Randomized Clinical Trial.

Importance: Dexamethasone initiated after the first week of life reduces the rate of death or bronchopulmonary dysplasia (BPD) but may cause long-term adverse effects in very preterm infants. Hydrocortisone is increasingly used as an alternative, but evidence supporting its efficacy and safety is lacking. Objective: To assess the effect of hydrocortisone initiated between 7 and 14 days after birth on death or BPD in very preterm infants. Design, Setting, and Participants: Double-blind, placebo-controlled randomized trial conducted in 19 neonatal intensive care units in the Netherlands and Belgium from November 15, 2011, to December 23, 2016, among preterm infants with a gestational age of less than 30 weeks and/or birth weight of less than 1250 g who were ventilator dependent between 7 and 14 days of life, with follow-up to hospital discharge ending December 12, 2017. Interventions: Infants were randomly assigned to receive a 22-day course of systemic hydrocortisone (cumulative dose, 72.5 mg/kg) (n = 182) or placebo (n = 190). Main Outcomes and Measures: The primary outcome was a composite of death or BPD assessed at 36 weeks' postmenstrual age. Twenty-nine secondary outcomes were analyzed up to hospital discharge, including death and BPD at 36 weeks' postmenstrual age. Results: Among 372 patients randomized (mean gestational age, 26 weeks; 55% male), 371 completed the trial; parents withdrew consent for 1 child treated with hydrocortisone. Death or BPD occurred in 128 of 181 infants (70.7%) randomized to hydrocortisone and in 140 of 190 infants (73.7%) randomized to placebo (adjusted risk difference, -3.6% [95% CI, -12.7% to 5.4%]; adjusted odds ratio, 0.87 [95% CI, 0.54-1.38]; P = .54). Of 29 secondary outcomes, 8 showed significant differences, including death at 36 weeks' postmenstrual age (15.5% with hydrocortisone vs 23.7% with placebo; risk difference, -8.2% [95% CI, -16.2% to -0.1%]; odds ratio, 0.59 [95% CI, 0.35-0.995]; P = .048). Twenty-one outcomes showed nonsignificant differences, including BPD (55.2% with hydrocortisone vs 50.0% with placebo; risk difference, 5.2% [95% CI, -4.9% to 15.2%]; odds ratio, 1.24 [95% CI, 0.82-1.86]; P = .31). Hyperglycemia requiring insulin therapy was the only adverse effect reported more often in the hydrocortisone group (18.2%) than in the placebo group (7.9%). Conclusions and Relevance: Among mechanically ventilated very preterm infants, administration of hydrocortisone between 7 and 14 days after birth, compared with placebo, did not improve the composite outcome of death or BPD at 36 weeks' postmenstrual age. These findings do not support the use of hydrocortisone for this indication. Trial Registration: Netherlands National Trial Register Identifier: NTR2768.

Early treatment versus expectative management of patent ductus arteriosus in preterm infants: a multicentre, randomised, non-inferiority trial in Europe (BeNeDuctus trial).

BACKGROUND: Much controversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants, especially in those born at a gestational age (GA) less than 28 weeks. No causal relationship has been proven between a (haemodynamically significant) PDA and neonatal complications related to pulmonary hyperperfusion and/or systemic hypoperfusion. Although studies show conflicting results, a common understanding is that medical or surgical treatment of a PDA does not seem to reduce the risk of major neonatal morbidities and mortality. As the PDA might have closed spontaneously, treated children are potentially exposed to iatrogenic adverse effects. A conservative approach is gaining interest worldwide, although convincing evidence to support its use is lacking. METHODS: This multicentre, randomised, non-inferiority trial is conducted in neonatal intensive care units. The study population consists of preterm infants (GA < 28 weeks) with an echocardiographic-confirmed PDA with a transductal diameter > 1.5 mm. Early treatment (between 24 and 72 h postnatal age) with the cyclooxygenase inhibitor (COXi) ibuprofen (IBU) is compared with an expectative management (no intervention intended to close a PDA). The primary outcome is the composite of mortality, and/or necrotising enterocolitis (NEC) Bell stage ≥ IIa, and/or bronchopulmonary dysplasia (BPD) defined as the need for supplemental oxygen, all at a postmenstrual age (PMA) of 36 weeks. Secondary outcome parameters are short term sequelae of cardiovascular failure, comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. Consequences regarding health economics are evaluated by cost effectiveness analysis and budget impact analysis. DISCUSSION: As a conservative approach is gaining interest, we investigate whether in preterm infants, born at a GA less than 28 weeks, with a PDA an expectative management is non-inferior to early treatment with IBU regarding to the composite outcome of mortality and/or NEC and/or BPD at a PMA of 36 weeks. TRIAL REGISTRATION: This trial is registered with the Dutch Trial Register NTR5479 (registered on 19 October 2015), the registry sponsored by the United States National Library of Medicine Clinicaltrials.gov NCT02884219 (registered May 2016) and the European Clinical Trials Database EudraCT 2017-001376-28 .

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants.

BACKGROUND: Respiratory failure due to lung immaturity is a major cause of mortality in preterm infants. Although the use of intermittent positive pressure ventilation (IPPV) in neonates with respiratory failure saves lives, its use is associated with lung injury and chronic lung disease. A newer form of ventilation called high frequency oscillatory ventilation has been shown in experimental studies to result in less lung injury. OBJECTIVES: The objective of this review was to determine the effect of the elective use of high frequency oscillatory ventilation (HFOV) as compared to conventional ventilation (CV) on the incidence of chronic lung disease (CLD), mortality and other complications associated with prematurity and assisted ventilation in preterm infants who were mechanically ventilated for respiratory distress syndrome (RDS). SEARCH METHODS: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross references, abstracts, conference and symposia proceedings; and from expert informants and handsearching of journals by The Cochrane Collaboration, mainly in the English language. The search was updated in January 2009 and again in November 2014. SELECTION CRITERIA: Randomised controlled trials comparing HFOV and CV in preterm or low birth weight infants with pulmonary dysfunction, mainly due to RDS, who required assisted ventilation. Randomisation and commencement of treatment needed to be as soon as possible after the start of CV and usually in the first 12 hours of life. DATA COLLECTION AND ANALYSIS: The methodological quality of each trial was independently reviewed by the review authors. The standard effect measures were relative risk (RR) and risk difference (RD). From 1/RD the number needed to benefit (NNTB) to produce one outcome was calculated. For all measures of effect, 95% confidence intervals (CIs) were used. For interpretation of subgroup analyses, a P value for subgroup differences as well as the I(2) statistic for between-subgroup heterogeneity were calculated. Meta-analysis was performed using both a fixed-effect and a random-effects model. Where heterogeneity was over 50%, the random-effects model RR was also reported. MAIN RESULTS: Nineteen eligible studies involving 4096 infants were included. Meta-analysis comparing HFOV with CV revealed no evidence of effect on mortality at 28 to 30 days of age or at approximately term equivalent age. These results were consistent across studies and in subgroup analyses. The risk of CLD in survivors at term equivalent gestational age was significantly reduced with the use of HFOV but this effect was inconsistent across studies, even after the meta-analysis was restricted to studies that applied a high lung volume strategy with HFOV. Subgroup analysis by HFOV strategy showed a similar effect in trials with a more strict lung volume recruitment strategy, targeting a very low fraction of inspired oxygen (FiO2), and trials with a less strict lung volume recruitment strategy and with a somewhat higher or unspecified target FiO2. Subgroup analyses by age at randomisation, routine surfactant use or not, type of high frequency ventilator (oscillator versus flow interrupter), inspiratory to expiratory (I:E) ratio of high frequency ventilator (1:1 versus 1:2) and CV strategy (lung protective or not) could not sufficiently explain the heterogeneity. Pulmonary air leaks, defined as gross air leaks or pulmonary interstitial emphysema, occurred more frequently in the HFOV group, whereas the risk of severe retinopathy of prematurity was significantly reduced.Although in some studies an increased risk of severe grade intracranial haemorrhage and periventricular leukomalacia was found, the overall meta-analysis revealed no significant differences in effect between HFOV and CV. The short-term neurological morbidity with HFOV was only found in the subgroup of two trials not using a high volume strategy with HFOV. Most trials did not find a significant difference in long-term neurodevelopmental outcome, although one recent trial showed a significant reduction in the risk of cerebral palsy and poor mental development. AUTHORS' CONCLUSIONS: There is evidence that the use of elective HFOV compared with CV results in a small reduction in the risk of CLD, but the evidence is weakened by the inconsistency of this effect across trials. Probably many factors, both related to the intervention itself as well as to the individual patient, interact in complex ways. In addition, the benefit could be counteracted by an increased risk of acute air leak. Adverse effects on short-term neurological outcomes have been observed in some studies but these effects are not significant overall. Most trials reporting long-term outcome have not identified any difference.

Effectiveness of body awareness interventions in fibromyalgia and chronic fatigue syndrome: a systematic review and meta-analysis.

OBJECTIVES: Patients with long-lasting pain problems often complain of lack of confidence and trust in their body. Through physical experiences and reflections they can develop a more positive body- and self-experience. Body awareness has been suggested as an approach for treating patients with chronic pain and other psychosomatic conditions. The aim of this systematic review is to assess the effectiveness of body awareness interventions (BAI) in fibromyalgia (FM) and chronic fatigue syndrome (CFS). METHODS: Two independent readers conducted a search on Medline, Cochrane Central, PsycINFO, Web of knowledge, PEDro and Cinahl for randomized controlled trials. RESULTS: We identified and screened 7.107 records of which 29 articles met the inclusion criteria. Overall, there is evidence that BAI has positive effects on the Fibromyalgia Impact Questionnaire (FIQ) (MD -5.55; CI -8.71 to -2.40), pain (SMD -0.39, CI -0.75 to -0.02), depression (SMD -0.23, CI -0.39 to -0.06), anxiety (SMD -0.23, CI -0.44 to -0.02) and Health Related Quality of Life (HRQoL) (SMD 0.62, CI 0.35-0.90) when compared with control conditions. The overall heterogeneity is very strong for FIQ (I(2) 92%) and pain (I(2) 97%), which cannot be explained by differences in control condition or type of BAI (hands-on/hands-off). The overall heterogeneity for anxiety, depression and HRQoL ranges from low to moderate (I(2) 0%-37%). CONCLUSIONS: Body awareness seems to play an important role in anxiety, depression and HRQoL. Still, interpretations have to be done carefully since the lack of high quality studies.

Clinical prediction models for bronchopulmonary dysplasia: a systematic review and external validation study.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth. Very different models using clinical parameters at an early postnatal age to predict BPD have been developed with little extensive quantitative validation. The objective of this study is to review and validate clinical prediction models for BPD. METHODS: We searched the main electronic databases and abstracts from annual meetings. The STROBE instrument was used to assess the methodological quality. External validation of the retrieved models was performed using an individual patient dataset of 3229 patients at risk for BPD. Receiver operating characteristic curves were used to assess discrimination for each model by calculating the area under the curve (AUC). Calibration was assessed for the best discriminating models by visually comparing predicted and observed BPD probabilities. RESULTS: We identified 26 clinical prediction models for BPD. Although the STROBE instrument judged the quality from moderate to excellent, only four models utilised external validation and none presented calibration of the predictive value. For 19 prediction models with variables matched to our dataset, the AUCs ranged from 0.50 to 0.76 for the outcome BPD. Only two of the five best discriminating models showed good calibration. CONCLUSIONS: External validation demonstrates that, except for two promising models, most existing clinical prediction models are poor to moderate predictors for BPD. To improve the predictive accuracy and identify preterm infants for future intervention studies aiming to reduce the risk of BPD, additional variables are required. Subsequently, that model should be externally validated using a proper impact analysis before its clinical implementation.

Celiac plexus neurolysis for abdominal cancer pain: a systematic review.

OBJECTIVE: This systematic review assesses the effectiveness and side effects of celiac plexus neurolysis (CPN) in the treatment of upper abdominal cancer pain, and evaluates whether there are any differences between the percutaneous and endoscopic ultrasound-guided (EUS) denervation techniques. METHODS: Five databases were searched, expanded by assessing the reference lists of all retrieved papers. Sixty-six publications fulfilled the inclusion/exclusion criteria and were included in the systematic review. Randomized controlled trials were available for the percutaneous CPN, and therefore meta-analyses were performed for pain, opioid consumption, and specific side effects. The quality of life data were too heterogeneous to be assessed by a meta-analysis, and evidence for EUS CPN could only be evaluated by observational studies. RESULTS: Meta-analyses show that percutaneous CPN significantly improves pain in patients with upper abdominal cancer, with a decrease in opioid consumption and side effects. It is unclear whether there is any change in quality of life. Case series suggest that EUS CPN improves pain. No conclusion can be made about EUS CPN's influence on opioid consumption. Although CPN is a safe procedure, side effects and complications can occur with both the percutaneous and EUS techniques. CONCLUSIONS: Following this review, evidence suggests that CPN should be considered in patients with upper abdominal cancer where the pain is not adequately controlled with systemic analgesics or when significant opioid-induced side effects are present. The percutaneous approach remains the standard technique as robust evidence for EUS CPN is lacking.

Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants (the SToP-BPD study); a multicenter randomized placebo controlled trial.

BACKGROUND: Randomized controlled trials have shown that treatment of chronically ventilated preterm infants after the first week of life with dexamethasone reduces the incidence of the combined outcome death or bronchopulmonary dysplasia (BPD). However, there are concerns that dexamethasone may increase the risk of adverse neurodevelopmental outcome. Hydrocortisone has been suggested as an alternative therapy. So far no randomized controlled trial has investigated its efficacy when administered after the first week of life to ventilated preterm infants. METHODS/DESIGN: The SToP-BPD trial is a randomized double blind placebo controlled multicenter study including 400 very low birth weight infants (gestational age < 30 weeks and/or birth weight < 1250 grams), who are ventilator dependent at a postnatal age of 7 - 14 days. Hydrocortisone (cumulative dose 72.5 mg/kg) or placebo is administered during a 22 day tapering schedule. Primary outcome measure is the combined outcome mortality or BPD at 36 weeks postmenstrual age. Secondary outcomes are short term effects on the pulmonary condition, adverse effects during hospitalization, and long-term neurodevelopmental sequelae assessed at 2 years corrected gestational age. Analysis will be on an intention to treat basis. DISCUSSION: This trial will determine the efficacy and safety of postnatal hydrocortisone administration at a moderately early postnatal onset compared to placebo for the reduction of the combined outcome mortality and BPD at 36 weeks postmenstrual age in ventilator dependent preterm infants.

Elective high-frequency oscillatory versus conventional ventilation in preterm infants: a systematic review and meta-analysis of individual patients' data.

BACKGROUND: Population and study design heterogeneity has confounded previous meta-analyses, leading to uncertainty about effectiveness and safety of elective high-frequency oscillatory ventilation (HFOV) in preterm infants. We assessed effectiveness of elective HFOV versus conventional ventilation in this group. METHODS: We did a systematic review and meta-analysis of individual patients' data from 3229 participants in ten randomised controlled trials, with the primary outcomes of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age, death or severe adverse neurological event, or any of these outcomes. FINDINGS: For infants ventilated with HFOV, the relative risk of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age was 0.95 (95% CI 0.88-1.03), of death or severe adverse neurological event 1.00 (0.88-1.13), or any of these outcomes 0.98 (0.91-1.05). No subgroup of infants (eg, gestational age, birthweight for gestation, initial lung disease severity, or exposure to antenatal corticosteroids) benefited more or less from HFOV. Ventilator type or ventilation strategy did not change the overall treatment effect. INTERPRETATION: HFOV seems equally effective to conventional ventilation in preterm infants. Our results do not support selection of preterm infants for HFOV on the basis of gestational age, birthweight for gestation, initial lung disease severity, or exposure to antenatal corticosteroids. FUNDING: Nestlé Belgium, Belgian Red Cross, and Dräger International.

Elective high-frequency oscillatory ventilation in preterm infants with respiratory distress syndrome: an individual patient data meta-analysis.

BACKGROUND: Despite the considerable amount of evidence from randomized controlled trials and meta-analyses, uncertainty remains regarding the efficacy and safety of high-frequency oscillatory ventilation as compared to conventional ventilation in the early treatment of respiratory distress syndrome in preterm infants. This results in a wide variation in the clinical use of high-frequency oscillatory ventilation for this indication throughout the world. The reasons are an unexplained heterogeneity between trial results and a number of unanswered, clinically important questions. Do infants with different risk profiles respond differently to high-frequency oscillatory ventilation? How does the ventilation strategy affect outcomes? Does the delay--either from birth or from the moment of intubation--to the start of high-frequency oscillation modify the effect of the intervention? Instead of doing new trials, those questions can be addressed by re-analyzing the individual patient data from the existing randomized controlled trials. METHODS/DESIGN: A systematic review with meta-analysis based on individual patient data. This involves the central collection, validation and re-analysis of the original individual data from each infant included in each randomized controlled trial addressing this question.The study objective is to estimate the effect of high-frequency oscillatory ventilation on the risk for the combined outcome of death or bronchopulmonary dysplasia or a severe adverse neurological event. In addition, it will explore whether the effect of high-frequency oscillatory ventilation differs by the infant's risk profile, defined by gestational age, intrauterine growth restriction, severity of lung disease at birth and whether or not corticosteroids were given to the mother prior to delivery. Finally, it will explore the importance of effect modifying factors such as the ventilator device, ventilation strategy and the delay to the start of high-frequency ventilation. DISCUSSION: An international collaborative group, the PreVILIG Collaboration (Prevention of Ventilator Induced Lung Injury Group), has been formed with the investigators of the original randomized trials to conduct this systematic review. In the field of neonatology, individual patient data meta-analysis has not been used previously. Final results are expected to be available by the end of 2009.

Medical end-of-life decisions in neonates and infants in Flanders.

BACKGROUND: Paediatricians are increasingly confronted with end-of-life decisions in critically ill neonates and infants. Little is known about the frequency and characteristics of end-of-life decisions in this population, nor about the relation with clinical and patients' characteristics. METHODS: A death-certificate study was done for all deaths of neonates and infants in the whole of Flanders over a 12 month period (August, 1999, to July, 2000). We sent an anonymous questionnaire by mail to the attending physician for each of the 292 children who died under the age of 1 year. Information on patients was obtained from national registers. An attitude study was done for all physicians who attended at least one death during the study period. FINDINGS: 253 (87%) of the 292 questionnaires were returned, and 121 (69%) of the 175 physicians involved completed the attitude questions. An end-of-life decision was possible in 194 (77%; 95% CI 70.4-82.4) of the 253 deaths studied, and such a decision was made in 143 cases (57%; 48.9-64.0). Lethal drugs were administered in 15 cases among 117 early neonatal deaths and in two cases among 77 later deaths (13%vs 3%; p=0.018). The attitude study showed that 95 (79%; 70.1-85.5) of the 121 physicians thought that their professional duty sometimes includes the prevention of unnecessary suffering by hastening death and 69 (58%; 48.1-66.5) of 120 supported legalisation of life termination in some cases. INTERPRETATION: Death of neonates and infants is commonly preceded by an end-of-life decision. The type of decision varied substantially according to the age of the child. Most physicians favour legalisation of the use of lethal drugs in some cases.

The T wave as a marker of dispersion of ventricular repolarization in premature infants before and while on treatment with the I(Kr) channel blocker cisapride.

AIMS: Measurement of electrocardiographic intervals to assess dispersion in ventricular repolarization may be helpful in the assessment of the risk of ventricular arrhythmia. We measured QTc, QT dispersion, and T wave intervals in premature infants before and while on treatment with the I(Kr) blocker cisapride as markers for dispersion in ventricular repolarization. METHODS AND RESULTS: We enrolled 15 non-ventilated premature infants with a mean gestational age of 30.5 weeks, ranging from 26.5 to 33.5 weeks, and mean postnatal age of 24 days, with a range from 5 to 51 days. A digital 12 lead electrocardiogram was recorded prior to and 3 days after administering cisapride at a dose of 0.8 mg/kg/day. Serum electrolytes were simultaneously measured. Electrocardiographic measurements before and after included: QT, QTc Bazett, QT dispersion, R-R, T wave interval peak to end, T wave interval peak to end/onset Q to T wave peak, T wave axis, T wave maximum voltage and QRS-T angle. A paired t test and analysis of variance was used to compare the variables before and during treatment. The QTc, T wave interval peak to end and the ratio T wave interval peak to end/onset Q to T peak increased significantly following treatment with cisapride. Results expressed as before and during treatment were for QTc: 429 (65) ms versus 454 (29) ms p < 0.02; for T wave interval peak to end: 65 (11) ms versus 103 (24) p <0.01, for the ratio T wave interval peak to end/onset Q to T peak: 0.32 (0.06) versus 0.55 (0.16) p < 0.001. Treatment with the I(Kr) blocker did not significantly alter the QT dispersion, T wave voltage, angle or QRS-T angle. CONCLUSION: The interval from the peak to the end of the T wave and the ratio of this value to the onset Q to T peak interval, represents regional dispersion of repolarization across the ventricular wall. This is a potentially useful clinical index in the assessment of arrhythmic risk in premature infants being treated by blockade of the I(Kr) channels.