Caffeine versus other methylxanthines for the prevention and treatment of apnea in preterm infants.

BACKGROUND: Methylxanthines, including caffeine, theophylline, and aminophylline, work as stimulants of the respiratory drive, and decrease apnea of prematurity, a developmental disorder common in preterm infants. In particular, caffeine has been reported to improve important clinical outcomes, including bronchopulmonary dysplasia (BPD) and neurodevelopmental disability. However, there is uncertainty regarding the efficacy of caffeine compared to other methylxanthines. OBJECTIVES: To assess the effects of caffeine compared to aminophylline or theophylline in preterm infants at risk of apnea, with apnea, or in the peri-extubation phase. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Epistemonikos, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and clinicaltrials.gov in February 2023. We also checked the reference lists of relevant articles to identify additional studies. SELECTION CRITERIA: Studies: randomized controlled trials (RCTs) and quasi-RCTs Participants: infants born before 34 weeks of gestation for prevention and extubation trials, and infants born before 37 weeks of gestation for treatment trials Intervention and comparison: caffeine versus theophylline or caffeine versus aminophylline. We included all doses and duration of treatment. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We evaluated treatment effects using a fixed-effect model with risk ratio (RR), risk difference (RD), and 95% confidence intervals (CI) for categorical data, and mean, standard deviation, and mean difference for continuous data. We used the GRADE approach to evaluate the certainty of evidence. MAIN RESULTS: We included 22 trials enrolling 1776 preterm infants. The indication for treatment was prevention of apnea in three studies, treatment of apnea in 13 studies, and extubation management in three studies. In three studies, there were multiple indications for treatment, and in one study, the indication for treatment was unclear. In 19 included studies, the infants had a mean gestational age between 28 and 32 weeks and a mean birth weight between 1000 g and 1500 g. One study's participants had a mean gestational age of more than 32 weeks, and two studies had participants with a mean birth weight of 1500 g or more. Caffeine administrated for any indication may result in little to no difference in all-cause mortality prior to hospital discharge compared to other methylxanthines (RR 1.12, 95% CI 0.68 to 1.84; RD 0.02, 95% CI -0.05 to 0.08; 2 studies, 396 infants; low-certainty evidence). Only one study enrolling 79 infants reported components of the outcome moderate to severe neurodevelopmental disability at 18 to 26 months. The evidence is very uncertain about the effect of caffeine on cognitive developmental delay compared to other methylxanthines (RR 0.17, 95% CI 0.02 to 1.37; RD -0.12, 95% CI -0.24 to 0.01; 1 study, 79 infants; very low-certainty evidence). The evidence is very uncertain about the effect of caffeine on language developmental delay compared to other methylxanthines (RR 0.76, 95% CI 0.37 to 1.58; RD -0.07, 95% CI -0.27 to 0.12; 1 study, 79 infants; very low-certainty evidence). The evidence is very uncertain about the effect of caffeine on motor developmental delay compared to other methylxanthines (RR 0.50, 95% CI 0.13 to 1.96; RD -0.07, 95% CI -0.21 to 0.07; 1 study, 79 infants; very low-certainty evidence). The evidence is very uncertain about the effect of caffeine on visual and hearing impairment compared to other methylxanthines. At 24 months of age, visual impairment was seen in 8 out of 11 infants and 10 out of 11 infants in the caffeine and other methylxanthines groups, respectively. Hearing impairment was seen in 2 out of 5 infants and 1 out of 1 infant in the caffeine and other methylxanthines groups, respectively. No studies reported the outcomes cerebral palsy, gross motor disability, and mental development. Compared to other methylxanthines, caffeine may result in little to no difference in BPD/chronic lung disease, defined as 28 days of oxygen exposure at 36 weeks' postmenstrual age (RR 1.40, 95% CI 0.92 to 2.11; RD 0.04, 95% CI -0.01 to 0.09; 3 studies, 481 infants; low-certainty evidence). The evidence is very uncertain about the effect of caffeine on side effects (tachycardia, agitation, or feed intolerance) leading to a reduction in dose or withholding of methylxanthines compared to other methylxanthines (RR 0.17, 95% CI 0.02 to 1.32; RD -0.29, 95% CI -0.57 to -0.02; 1 study, 30 infants; very low-certainty evidence). Caffeine may result in little to no difference in duration of hospital stay compared to other methylxanthines (median (interquartile range): caffeine 43 days (27.5 to 61.5); other methylxanthines 39 days (28 to 55)). No studies reported the outcome seizures. AUTHORS' CONCLUSIONS: Although caffeine has been shown to improve important clinical outcomes, in the few studies that compared caffeine to other methylxanthines, there might be little to no difference in mortality, bronchopulmonary dysplasia, and duration of hospital stay. The evidence is very uncertain about the effect of caffeine compared to other methylxanthines on long-term development and side effects. Although caffeine or other methylxanthines are widely used in preterm infants, there is little direct evidence to support the choice of which methylxanthine to use. More research is needed, especially on extremely preterm infants born before 28 weeks of gestation. Data from four ongoing studies might provide more evidence on the effects of caffeine or other methylxanthines.

Comparison of environmental impacts related to municipal solid waste and construction and demolition waste management and recycling in a Latin American developing city.

Construction and demolition waste (CDW) and municipal solid waste (MSW) are the waste flows mostly generated at a global level. In developing countries, most of these waste streams are disposed of in open dumps. Policy-makers should be informed in which priorities should be established in order to improve the quality of the environment. The current research compares the environmental impacts generated by the MSW and CDW management system of La Paz (Bolivia). The aim is to evaluate (1) which environmental impact indicators are more important per waste flow and (2) if recycling can be considered a good option for mitigating such environmental footprint. A life cycle assessment (LCA) of the formal MSW management and the CDW mismanagement (i.e., open dumping) were conducted. The analysis of the management system (2019) is compared with future developments in recycling that counts with the support of an international cooperative project financed by the Italian cooperation. Results reported that, at a municipal level, CDW mismanagement contributes more than 60% to the freshwater aquatic ecotoxicity, which represents the most relevant impact generated by this waste stream. Recycling allows achieving avoided impacts higher than the ones produced for three of six environmental impacts, suggesting MSW and CDW recovery as an important option for preventing environmental degradation. The research is the first attempt to highlight the importance of organizing appropriate CDW management systems into an integrated waste management scheme for mitigating environmental impacts in developing cities.

Interventions for the management of transient tachypnoea of the newborn - an overview of systematic reviews.

BACKGROUND: Transient tachypnoea of the newborn (TTN) is characterised by tachypnoea and signs of respiratory distress. It is caused by delayed clearance of lung fluid at birth. TTN typically appears within the first two hours of life in term and late preterm newborns. Although it is usually a self-limited condition, admission to a neonatal unit is frequently required for monitoring, the provision of respiratory support, and drugs administration. These interventions might reduce respiratory distress during TTN and enhance the clearance of lung liquid. The goals are reducing the effort required to breathe, improving respiratory distress, and potentially shortening the duration of tachypnoea. However, these interventions might be associated with harm in the infant. OBJECTIVES: The aim of this overview was to evaluate the benefits and harms of different interventions used in the management of TTN. METHODS: We searched the Cochrane Database of Systematic Reviews on 14 July 2021 for ongoing and published Cochrane Reviews on the management of TTN in term (> 37 weeks' gestation) or late preterm (34 to 36 weeks' gestation) infants. We included all published Cochrane Reviews assessing the following categories of interventions administered within the first 48 hours of life: beta-agonists (e.g. salbutamol and epinephrine), corticosteroids, diuretics, fluid restriction, and non-invasive respiratory support. The reviews compared the above-mentioned interventions to placebo, no treatment, or other interventions for the management of TTN. The primary outcomes of this overview were duration of tachypnoea and the need for mechanical ventilation. Two overview authors independently checked the eligibility of the reviews retrieved by the search and extracted data from the included reviews using a predefined data extraction form. Any disagreements were resolved by discussion with a third overview author. Two overview authors independently assessed the methodological quality of the included reviews using the AMSTAR 2 (A MeaSurement Tool to Assess systematic Reviews) tool. We used the GRADE approach to assess the certainty of evidence for effects of interventions for TTN management. As all of the included reviews reported summary of findings tables, we extracted the information already available and re-graded the certainty of evidence of the two primary outcomes to ensure a homogeneous assessment. We provided a narrative summary of the methods and results of each of the included reviews and summarised this information using tables and figures. MAIN RESULTS: We included six Cochrane Reviews, corresponding to 1134 infants enrolled in 18 trials, on the management of TTN in term and late preterm infants, assessing salbutamol (seven trials), epinephrine (one trial), budesonide (one trial), diuretics (two trials), fluid restriction (four trials), and non-invasive respiratory support (three trials). The quality of the included reviews was high, with all of them fulfilling the critical domains of the AMSTAR 2. The certainty of the evidence was very low for the primary outcomes, due to the imprecision of the estimates (few, small included studies) and unclear or high risk of bias. Salbutamol may reduce the duration of tachypnoea compared to placebo (mean difference (MD) -16.83 hours, 95% confidence interval (CI) -22.42 to -11.23, 2 studies, 120 infants, low certainty evidence). We did not identify any review that compared epinephrine or corticosteroids to placebo and reported on the duration of tachypnoea. However, one review reported on "trend of normalisation of respiratory rate", a similar outcome, and found no differences between epinephrine and placebo (effect size not reported). The evidence is very uncertain regarding the effect of diuretics compared to placebo (MD -1.28 hours, 95% CI -13.0 to 10.45, 2 studies, 100 infants, very low certainty evidence). We did not identify any review that compared fluid restriction to standard fluid rates and reported on the duration of tachypnoea. The evidence is very uncertain regarding the effect of continuous positive airway pressure (CPAP) compared to free-flow oxygen therapy (MD -21.1 hours, 95% CI -22.9 to -19.3, 1 study, 64 infants, very low certainty evidence); the effect of nasal high-frequency (oscillation) ventilation (NHFV) compared to CPAP (MD -4.53 hours, 95% CI -5.64 to -3.42, 1 study, 40 infants, very low certainty evidence); and the effect of nasal intermittent positive pressure ventilation (NIPPV) compared to CPAP on duration of tachypnoea (MD 4.30 hours, 95% CI -19.14 to 27.74, 1 study, 40 infants, very low certainty evidence). Regarding the need for mechanical ventilation, the evidence is very uncertain for the effect of salbutamol compared to placebo (risk ratio (RR) 0.60, 95% CI 0.13 to 2.86, risk difference (RD) 10 fewer, 95% CI 50 fewer to 30 more per 1000, 3 studies, 254 infants, very low certainty evidence); the effect of epinephrine compared to placebo (RR 0.67, 95% CI 0.08 to 5.88, RD 70 fewer, 95% CI 460 fewer to 320 more per 1000, 1 study, 20 infants, very low certainty evidence); and the effect of corticosteroids compared to placebo (RR 0.52, 95% CI 0.05 to 5.38, RD 40 fewer, 95% CI 170 fewer to 90 more per 1000, 1 study, 49 infants, very low certainty evidence). We did not identify a review that compared diuretics to placebo and reported on the need for mechanical ventilation. The evidence is very uncertain regarding the effect of fluid restriction compared to standard fluid administration (RR 0.73, 95% CI 0.24 to 2.23, RD 20 fewer, 95% CI 70 fewer to 40 more per 1000, 3 studies, 242 infants, very low certainty evidence); the effect of CPAP compared to free-flow oxygen (RR 0.30, 95% CI 0.01 to 6.99, RD 30 fewer, 95% CI 120 fewer to 50 more per 1000, 1 study, 64 infants, very low certainty evidence); the effect of NIPPV compared to CPAP (RR 4.00, 95% CI 0.49 to 32.72, RD 150 more, 95% CI 50 fewer to 350 more per 1000, 1 study, 40 infants, very low certainty evidence); and the effect of NHFV versus CPAP (effect not estimable, 1 study, 40 infants, very low certainty evidence). Regarding our secondary outcomes, duration of hospital stay was the only outcome reported in all of the included reviews. One trial on fluid restriction reported a lower duration of hospitalisation in the restricted-fluids group, but with very low certainty of evidence. The evidence was very uncertain for the effects on secondary outcomes for the other five reviews. Data on potential harms were scarce, as all of the trials were underpowered to detect possible increases in adverse events such as pneumothorax, arrhythmias, and electrolyte imbalances. No adverse effects were reported for salbutamol; however, this medication is known to carry a risk of tachycardia, tremor, and hypokalaemia in other settings. AUTHORS' CONCLUSIONS: This overview summarises the evidence from six Cochrane Reviews of randomised trials regarding the effects of postnatal interventions in the management of TTN. Salbutamol may reduce the duration of tachypnoea slightly. We are uncertain as to whether salbutamol reduces the need for mechanical ventilation. We are uncertain whether epinephrine, corticosteroids, diuretics, fluid restriction, or non-invasive respiratory support reduces the duration of tachypnoea and the need for mechanical ventilation, due to the extremely limited evidence available. Data on harms were lacking.

Cuffed versus uncuffed endotracheal tubes for neonates.

BACKGROUND: Endotracheal intubation is a commonly performed procedure in neonates, the risks of which are well-described. Some endotracheal tubes (ETT) are equipped with a cuff that can be inflated after insertion of the ETT in the airway to limit leak or aspiration. Cuffed ETTs have been shown in larger children and adults to reduce gas leak around the ETT, ETT exchange, accidental extubation, and exposure of healthcare workers to anesthetic gas during surgery. With improved understanding of neonatal airway anatomy and the widespread use of cuffed ETTs by anesthesiologists, the use of cuffed tubes is increasing in neonates. OBJECTIVES: To assess the benefits and harms of cuffed ETTs (inflated or non-inflated) compared to uncuffed ETTs for respiratory support in neonates. SEARCH METHODS: We searched CENTRAL, PubMed, and CINAHL on 20 August 2021; we also searched trial registers and checked reference lists to identify additional studies. SELECTION CRITERIA: We included randomized controlled trials (RCTs), quasi-RCTs, and cluster-randomized trials comparing cuffed (inflated and non-inflated) versus uncuffed ETTs in newborns. We sought to compare 1. inflated, cuffed versus uncuffed ETT; 2. non-inflated, cuffed versus uncuffed ETT; and 3. inflated, cuffed versus non-inflated, cuffed ETT. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane Neonatal. Two review authors independently assessed studies identified by the search strategy for inclusion, extracted data, and assessed risk of bias. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We identified one eligible RCT for inclusion that compared the use of cuffed (inflated if ETT leak greater than 20% with cuff pressure 20 cm H2O or less) versus uncuffed ETT. The author provided a spreadsheet with individual data. Among 76 infants in the original manuscript, 69 met the inclusion and exclusion criteria for this Cochrane Review. We found possible bias due to lack of blinding and other bias. We are very uncertain about frequency of postextubation stridor, because the confidence intervals (CI) of the risk ratio (RR) were very wide (RR 1.36, 95% CI 0.35 to 5.25; risk difference (RD) 0.03, -0.11 to 0.18; 1 study, 69 participants; very low-certainty evidence). No neonate was diagnosed with postextubation subglottic stenosis; however, endoscopy was not available to confirm the clinical diagnosis. We are very uncertain about reintubation for stridor or subglottic stenosis because the CIs of the RR were very wide (RR 0.27, 95% CI 0.01 to 6.49; RD -0.03, 95% CI -0.11 to 0.05; 1 study, 69 participants; very low-certainty evidence). No neonate had surgical intervention (e.g. endoscopic balloon dilation, cricoid split, tracheostomy) for stridor or subglottic stenosis (1 study, 69 participants). Neonates randomized to cuffed ETT may be less likely to have a reintubation for any reason (RR 0.06, 95% CI 0.01 to 0.45; RD -0.39, 95% CI -0.57 to -0.21; number needed to treat for an additional beneficial outcome 3, 95% CI 2 to 5; 1 study, 69 participants; very low-certainty evidence). We are very uncertain about accidental extubation because the CIs of the RR were wide (RR 0.82, 95% CI 0.12 to 5.46; RD -0.01, 95% CI -0.12 to 0.10; 1 study, 69 participants; very low-certainty evidence). We are very uncertain about all-cause mortality during initial hospitalization because the CIs of the RR were extremely wide (RR 2.46, 95% CI 0.10 to 58.39; RD 0.03, 95% CI -0.05 to 0.10; 1 study, 69 participants; very low-certainty evidence). There is one ongoing trial. We classified two studies as awaiting classification because outcome data were not reported separately for newborns and older infants. AUTHORS' CONCLUSIONS: Evidence for comparing cuffed versus uncuffed ETTs in neonates is limited by a small number of babies in a single RCT with possible bias. There is very low certainty evidence for all outcomes of this review. CIs of the estimate for postextubation stridor were wide. No neonate had clinical evidence for subglottic stenosis; however, endoscopy results were not available to assess the anatomy. Additional RCTs are necessary to evaluate the benefits and harms of cuffed ETTs (inflated and non-inflated) in the neonatal population. These studies must include neonates and be conducted both for short-term use (in the setting of the operating room) and chronic use (in the setting of chronic lung disease) of cuffed ETTs.

Environmental assessment of construction and demolition waste recycling in Bolivia: Focus on transportation distances and selective collection rates.

Construction and demolition waste (CDW) management in developing countries is a global concern. The analysis of scenarios and the implementation of life cycle assessment (LCA) support decision-makers in introducing integrated CDW management systems. This paper introduces the application of an LCA in La Paz (Bolivia), where CDW is mainly dumped in open areas. The aim of the research is to evaluate the benefits of inert CDW recycling in function of the selective collection rate, defined as the amount of waste (%wt.) sorted at the source in relation to the total waste amount produced, and the distances from the CDW generation to the material recycling facility. The outcomes of the research suggest that increasing the selective collection rates (5% to 99%) spread the importance of transportation distances planning since it affects the magnitude of the environmental impacts (1.05 tCO2-eq to 20.7 tCO2-eq per km traveled). Transportation limits have been found to be lower than about 40 km in order to make recycling beneficial for all environmental impacts and for all selective collection rate, with the eutrophication potential as the limiting indicator. The theoretical analysis suggests implementing LCA with primary data and involving statistics related to the transportation of virgin materials avoided thanks to recycling. The outcomes of the research support the implementation of CDW recycling in developing countries since it has been found that material recovery is always beneficial.

Sensitivity analysis and improvements of the recycling rate in municipal solid waste life cycle assessment: Focus on a Latin American developing context.

The life cycle assessment (LCA) of municipal solid waste (MSW) systems in developing countries is a matter of research. Obtain reliable results is challenging since field data and local databases are not always available. The research presented in this paper explores this issue in La Paz (Bolivia), where six environmental impact categories were assessed. The LCA, related to the formal MSW management system of the city, involves a sensitivity analysis of ten parameters and the scenario assessment in relation to the increase of the recycling rate. Results report that the environmental impacts are mostly sensitive in relation to landfill gas collection efficiency, use of plastic bags, the transportation distances of collected waste, and the replacement rate of virgin materials. Global warming potential is the impact category most variable (341.38-551.95 kg CO2-eq tMSW-1), although it is not considerably reduced by recycling, which contributed mostly to the human toxicity and freshwater aquatic ecotoxicity. Doubling the amount of MSW recycled, from 235 t to about 473 t per year, human toxicity potential reduces of about 18% while freshwater aquatic ecotoxicity of about 12%. This research contributes for evaluating the most sensitive parameters in an MSW-LCA and to support policymakers towards waste recycling and sustainable development in Latin America developing cities.

Salbutamol for transient tachypnea of the newborn.

BACKGROUND: Transient tachypnea of the newborn is characterized by tachypnea and signs of respiratory distress. Transient tachypnea typically appears within the first two hours of life in term and late preterm newborns. Although transient tachypnea of the newborn is usually a self-limited condition, it is associated with wheezing syndromes in late childhood. The rationale for the use of salbutamol (albuterol) for transient tachypnea of the newborn is based on studies showing that ß-agonists can accelerate the rate of alveolar fluid clearance. This review was originally published in 2016 and updated in 2020. OBJECTIVES: To assess whether salbutamol compared to placebo, no treatment or any other drugs administered to treat transient tachypnea of the newborn, is effective and safe for infants born at 34 weeks' gestational age with this diagnosis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2020, Issue 4) in the Cochrane Library; PubMed (1996 to April 2020), Embase (1980 to April 2020); and CINAHL (1982 to April 2020). We applied no language restrictions. We searched the abstracts of the major congresses in the field (Perinatal Society of Australia New Zealand and Pediatric Academic Societies) from 2000 to 2020 and clinical trial registries. SELECTION CRITERIA: Randomized controlled trials, quasi-randomized controlled trials and cluster trials comparing salbutamol versus placebo or no treatment or any other drugs administered to infants born at 34 weeks' gestational age or more and less than three days of age with transient tachypnea of the newborn. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology for data collection and analysis. The primary outcomes considered in this review were duration of oxygen therapy, need for continuous positive airway pressure and need for mechanical ventilation. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: Seven trials, which included 498 infants, met the inclusion criteria. All trials compared a nebulized dose of salbutamol with normal saline. Four studies used one single dose of salbutamol; in two studies, three to four doses were provided; in one study, additional doses were administered if needed. The certainty of the evidence was low for duration of hospital stay and very low for the other outcomes. Among the primary outcomes of this review, four trials (338 infants) reported the duration of oxygen therapy, (mean difference (MD) -19.24 hours, 95% confidence interval (CI) -23.76 to -14.72); one trial (46 infants) reported the need for continuous positive airway pressure (risk ratio (RR) 0.73, 95% CI 0.38 to 1.39; risk difference (RD) -0.15, 95% CI -0.45 to 0.16), and three trials (254 infants) reported the need for mechanical ventilation (RR 0.60, 95% CI 0.13 to 2.86; RD -0.01, 95% CI -0.05 to 0.03). Both duration of hospital stay (4 trials; 338 infants) and duration of respiratory support (2 trials, 228 infants) were shorter in the salbutamol group (MD -1.48, 95% CI -1.8 to -1.16; MD -9.24, 95% CI -14.24 to -4.23, respectively). One trial (80 infants) reported duration of mechanical ventilation and pneumothorax but data could not be extracted due to the reporting of these outcomes (type of units of effect measure and unclear number of events, respectively). Five trials are ongoing. AUTHORS' CONCLUSIONS: There was limited evidence to establish the benefits and harms of salbutamol in the management of transient tachypnea of the newborn. We are uncertain whether salbutamol administration reduces the duration of oxygen therapy, duration of tachypnea, need for continuous positive airway pressure and for mechanical ventilation. Salbutamol may slightly reduce hospital stay. Five trials are ongoing. Given the limited and low certainty of the evidence available, we could not determine whether salbutamol was safe or effective for the treatment of transient tachypnea of the newborn.

Pharmacological treatment for continuous spike-wave during slow wave sleep syndrome and Landau-Kleffner Syndrome.

BACKGROUND: Continuous spike-wave during slow wave sleep syndrome (CSWS) and Landau-Kleffner syndrome (LKS) are two epileptic encephalopathies that present with neurocognitive regression, aphasia, and clinical seizures, typically presenting in children around five years of age. The pathophysiology of these conditions is not completely understood. Some studies suggest a common origin for both. No systematic reviews have assessed the efficacy of pharmacological interventions for these conditions. OBJECTIVES: To assess the benefit and adverse effects of pharmacological interventions for the treatment of CSWS and LKS. SEARCH METHODS: On 8 September 2020, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE Ovid (1946 to September 04, 2020). We applied no language restrictions. CRS Web includes randomised or quasi-randomised, controlled trials from CENTRAL, PubMed, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. SELECTION CRITERIA: Randomised controlled trials, quasi-randomised controlled trials, and cluster-randomised trials comparing antiepileptic drugs alone, or with steroids or intravenous immunoglobulins, or both versus other antiepileptic drugs, or placebo, or no treatment, administered to children with CSWS and LKS. We planned to compare treatments for the two conditions separately. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies identified by the search strategy for inclusion. The primary outcomes considered in this review were neuropsychological-neurolinguistic functions. MAIN RESULTS: Our search strategy yielded 18 references. Two review authors independently assessed all references. We did not find any completed studies to include. We identified one ongoing trial, which was terminated because of lack of enrolment. AUTHORS' CONCLUSIONS: There was no evidence from trials to support or refute the use of pharmacological treatment for continuous spike-wave during slow wave sleep syndrome or Landau-Kleffner syndrome. Well-designed randomised controlled trials are needed to inform practice.

Non-invasive respiratory support for the management of transient tachypnea of the newborn.

BACKGROUND: Transient tachypnea of the newborn (TTN) is characterized by tachypnea and signs of respiratory distress. Transient tachypnea typically appears within the first two hours of life in term and late preterm newborns. Supportive management might be sufficient. Non-invasive (i.e. without endotracheal intubation) respiratory support may, however, be administered to reduce respiratory distress during TTN. In addition, non-invasive respiratory support might improve clearance of lung liquid thus reducing the effort required to breathe, improving respiratory distress and potentially reducing the duration of tachypnea. OBJECTIVES: To assess benefits and harms of non-invasive respiratory support for the management of transient tachypnea of the newborn. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 2), MEDLINE (1996 to 19 February 2019), Embase (1980 to 19 February 2019) and CINAHL (1982 to 19 February 2019). We applied no language restrictions. We searched clinical trial registries for ongoing studies. SELECTION CRITERIA: Randomized controlled trials, quasi-randomized controlled trials and cluster trials on non-invasive respiratory support provided to infants born at 34 weeks' gestational age or more and less than three days of age with transient tachypnea of the newborn. DATA COLLECTION AND ANALYSIS: For each of the included trials, two review authors independently extracted data (e.g. number of participants, birth weight, gestational age, duration of oxygen therapy, need for continuous positive airway pressure [CPAP] and need for mechanical ventilation, duration of mechanical ventilation, etc.) and assessed the risk of bias (e.g. adequacy of randomization, blinding, completeness of follow-up). The primary outcomes considered in this review were need for mechanical ventilation and pneumothorax. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included three trials (150 infants) comparing either CPAP to free-flow oxygen, nasal intermittent mandatory ventilation to nasal CPAP, or nasal high-frequency percussive ventilation versus nasal CPAP. Due to these different comparisons and to high clinical heterogeneity in the baseline clinical characteristics, we did not pool the three studies. The use of CPAP versus free oxygen did not improve the primary outcomes of this review: need for mechanical ventilation (risk ratio [RR] 0.30, 95% confidence interval [CI] 0.01 to 6.99; 1 study, 64 participants); and pneumothorax (not estimable, no cases occurred). Among secondary outcomes, CPAP reduced the duration of tachypnea as compared to free oxygen (mean difference [MD] -21.10 hours, 95% CI -22.92 to -19.28; 1 study, 64 participants). Nasal intermittent ventilation did not reduce the need for mechanical ventilation as compared with CPAP (RR 4.00, 95% CI 0.49 to 32.72; 1 study, 40 participants) or the incidence of pneumothorax (RR 1.00, 95% CI 0.07 to 14.90; 1 study, 40 participants); duration of tachypnea did not differ (MD 4.30, 95% CI -19.14 to 27.74; 1 study, 40 participants). In the study comparing nasal high-frequency ventilation to CPAP, no cases of mechanical ventilation of pneumothorax occurred (not estimable; 1 study, 46 participants); duration of tachypnea was reduced in the nasal high-frequency ventilation group (MD -4.53, 95% CI -5.64 to -3.42; 1 study, 46 participants). The quality of the evidence was very low due to the imprecision of the estimates and unclear risk of bias for detection bias and high risk of bias for reporting bias. Tests for heterogeneity were not applicable for any of the analyses as no studies were pooled. Two trials are ongoing. AUTHORS' CONCLUSIONS: There is insufficient evidence to establish the benefit and harms of non-invasive respiratory support in the management of transient tachypnea of the newborn. Though two of the included trials showed a shorter duration of tachypnea, clinically relevant outcomes did not differ amongst the groups. Given the limited and low quality of the evidence available, it was impossible to determine whether non-invasive respiratory support was safe or effective for the treatment of transient tachypnea of the newborn.

Postnatal corticosteroids for transient tachypnoea of the newborn.

BACKGROUND: Transient tachypnoea of the newborn (TTN) is characterized by tachypnoea and signs of respiratory distress. Transient tachypnoea typically appears within the first two hours of life in term and late preterm newborns. The administration of corticosteroids might compensate for the impaired hormonal changes which occur when infants are delivered late preterm, or at term but before the onset of spontaneous labour (elective caesarean section). Corticosteroids might improve the clearance of liquid from the lungs, thus reducing the effort required to breathe and improving respiratory distress. OBJECTIVES: The objective of this review is to assess whether postnatal corticosteroids - compared to placebo, no treatment or any other drugs administered to treat TTN - are effective and safe in the treatment of TTN in infants born at 34 weeks' gestational age or more. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 2), MEDLINE (1996 to 19 February 2019), Embase (1980 to 19 February 2019) and CINAHL (1982 to 19 February 2019). We applied no language restrictions. We searched clinical trial registries for ongoing studies. SELECTION CRITERIA: We included randomized controlled trials, quasi-randomized controlled trials and cluster-randomized trials comparing postnatal corticosteroids versus placebo or no treatment or any other drugs administered to infants born at 34 weeks' gestational age or more and less than three days of age with TTN. DATA COLLECTION AND ANALYSIS: For each of the included trials, two review authors independently extracted data (e.g. number of participants, birth weight, gestational age, duration of oxygen therapy, need for continuous positive airway pressure, need for mechanical ventilation, duration of mechanical ventilation, etc.) and assessed the risk of bias (e.g. adequacy of randomization and blinding, completeness of follow-up). The primary outcomes considered in this review were need for nasal continuous positive airway pressure and need for mechanical ventilation. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: One trial, which included 49 infants, met the inclusion criteria. The trial compared the use of inhaled corticosteroids (budesonide) with placebo. We found no differences between groups in terms of need for nasal continuous positive airway pressure (risk ratio (RR) 1.27, 95% confidence interval (CI) 0.65 to 2.51; 1 study, 49 participants) and need for mechanical ventilation (RR 0.52, 95% CI 0.05 to 5.38; 1 study, 49 participants). The type of mechanical ventilation used in the included study was high-frequency oscillation. Tests for heterogeneity were not applicable for any of the analyses as only one study was included. Out of the secondary outcomes we deemed to be of greatest importance to patients, the study only reported on duration of hospital stay, which was no different between groups. The quality of the evidence is very low, due to the imprecision of the estimates and indirectness. We identified no ongoing trials. AUTHORS' CONCLUSIONS: Given the paucity and very low quality of the available evidence, we are unable to determine the benefits and harms of postnatal administration of either inhaled or systemic corticosteroids for the management of TTN.

Salbutamol for transient tachypnea of the newborn.

BACKGROUND: Transient tachypnea of the newborn is characterized by tachypnea and signs of respiratory distress. Transient tachypnea typically appears within the first two hours of life in term and late preterm newborns. Although transient tachypnea of the newborn is usually a self limited condition, it is associated with wheezing syndromes in late childhood. The rationale for the use of salbutamol (albuterol) for transient tachypnea of the newborn is based on studies showing that ß-agonists can accelerate the rate of alveolar fluid clearance. OBJECTIVES: To assess whether salbutamol compared to placebo, no treatment or any other drugs administered to treat transient tachypnea of the newborn, is effective and safe in the treatment of transient tachypnea of the newborn in infants born at 34 weeks' gestational age or more. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2016, Issue 3), MEDLINE (1996 to March 2016), EMBASE (1980 to March 2016) and CINAHL (1982 to March 2016). We applied no language restrictions. We searched the abstracts of the major congresses in the field (Perinatal Society of Australia New Zealand and Pediatric Academic Societies) from 2000 to 2015 and clinical trial registries. SELECTION CRITERIA: Randomized controlled trials, quasi-randomized controlled trials and cluster trials comparing salbutamol versus placebo or no treatment or any other drugs administered to infants born at 34 weeks' gestational age or more and less than three days of age with transient tachypnea of the newborn. DATA COLLECTION AND ANALYSIS: For each of the included trials, two review authors independently extracted data (e.g. number of participants, birth weight, gestational age, duration of oxygen therapy, need for continuous positive airway pressure and need for mechanical ventilation, duration of mechanical ventilation, etc.) and assessed the risk of bias (e.g. adequacy of randomization, blinding, completeness of follow-up). The primary outcomes considered in this review were duration of oxygen therapy, need for continuous positive airway pressure and need for mechanical ventilation. MAIN RESULTS: Three trials, which included 140 infants, met the inclusion criteria. All three trials compared a nebulized dose of salbutamol with placebo; in one of the three trials newborns were assigned to two different doses of the intervention. We found differences in the duration of oxygen therapy (mean difference (MD) -43.10 hours, 95% confidence interval (CI) -81.60 to -4.60). There were no differences in the need for continuous positive airway pressure (risk ratio (RR) 0.73, 95% CI 0.38 to 1.39; risk difference (RD) -0.15, 95% CI -0.45 to 0.16; 1 study, 46 infants) or the need for mechanical ventilation (RR 1.50, 95% CI 0.06 to 34.79; RD 0.03, 95% CI -0.08 to 0.14; 1 study, 46 infants). Tests for heterogeneity were not applicable for any of the analyses as only one study was included. Among secondary outcomes, we found no differences in terms of duration of hospital stay and tachypnea. The quality of the evidence was very low due to the imprecision of the estimates. One trial is ongoing. AUTHORS' CONCLUSIONS: At present there is insufficient evidence to determine the efficacy and safety of salbutamol in the management of transient tachypnea of the newborn. The quality of evidence was low due to paucity of included trials, small sample sizes and overall poor methodologic quality.

Epinephrine for transient tachypnea of the newborn.

BACKGROUND: Transient tachypnea of the newborn is characterized by tachypnea and signs of respiratory distress. Transient tachypnea typically appears within the first two hours of life in term and late preterm newborns. Although transient tachypnea of the newborn is usually a self limited condition, it is associated with wheezing syndromes in late childhood. The rationale for the use of epinephrine (adrenaline) for transient tachypnea of the newborn is based on studies showing that ß-agonists can accelerate the rate of alveolar fluid clearance. OBJECTIVES: To assess whether epinephrine compared to placebo, no treatment or any other drugs (excluding salbutamol) is effective and safe in the treatment of transient tachypnea of the newborn in infants born at 34 weeks' gestational age or more. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2016, Issue 3), MEDLINE (1996 to March 2016), EMBASE (1980 to March 2016) and CINAHL (1982 to March 2016). We applied no language restrictions. We searched the abstracts of the major congresses in the field (Perinatal Society of Australia and New Zealand and Pediatric Academic Societies) from 2000 to 2015. SELECTION CRITERIA: Randomized controlled trials, quasi-randomized controlled trials and cluster trials comparing epinephrine versus placebo or no treatment or any other drugs administered to infants born at 34 weeks' gestational age or more and less than three days of age with transient tachypnea of the newborn. DATA COLLECTION AND ANALYSIS: For the included trial, two review authors independently extracted data (e.g. number of participants, birth weight, gestational age, duration of oxygen therapy (hours), need for continuous positive airway pressure and need for mechanical ventilation, duration of mechanical ventilation, etc.) and assessed the risk of bias (e.g. adequacy of randomization, blinding, completeness of follow-up). The primary outcomes considered in this review were duration of oxygen therapy (hours), need for continuous positive airway pressure and need for mechanical ventilation. MAIN RESULTS: One trial, which included 20 infants, met the inclusion criteria of this review. Study authors administered three doses of nebulized 2.25% racemic epinephrine or placebo. We found no differences between the two group in the duration of supplemental oxygen therapy (mean difference (MD) -6.60, 95% confidence interval (CI) -54.80 to 41.60 hours) and need for mechanical ventilation (risk ratio (RR) 0.67, 95% CI 0.08 to 5.88; risk difference (RD) -0.07, 95% CI -0.46 to 0.32). Among secondary outcomes, we found no differences in terms of initiation of oral feeding. The quality of the evidence was limited due to the imprecision of the estimates. AUTHORS' CONCLUSIONS: At present there is insufficient evidence to determine the efficacy and safety of epinephrine in the management of transient tachypnea of the newborn.

Health technology assessment of computer-assisted pap test screening in Italy.

OBJECTIVE: To assess the introduction of computer-assisted Pap test screening in cervical cancer screening. Various scenarios are considered: conventional and liquid-based cytology (LBC) slides, fully automatic instrumentation (Becton Dickinson FocalPoint™ Slide Profiler and Hologic ThinPrep® Imaging System), and semiautomatic scanner (Hologic Integrated Imager I-Squared). METHODS: A working group was formed that included researchers from the largest centers already using instrumentation. A questionnaire on laboratory management and on social/ethical issues and annual workload was proposed. Prices for the technology were obtained directly from the producers; costs were calculated from observed and literature data. The scope of the report and final draft were submitted to a consulting committee of stakeholders. RESULTS: The break-even point was found to be 49,000 cases/year, if conventional slides were used, while it was near the theoretical maximum capacity, 70,000 cases/year, with LBC slides. Efficiency increased with the volume of slides. Screening time decreased by two thirds for conventional slides and by less than half for LBC slides. Acceptance of the instrumentation by the users was good. CONCLUSIONS: Computer-assisted screening may increase productivity even if in most situations it will mean additional costs. Furthermore, primary screening with human papillomavirus tests will drastically reduce the need for Pap test reading.

[Health technology assessment report: Computer-assisted Pap test for cervical cancer screening]. / Health technology assessment report: Pap test con lettura computer-assistita per lo screening del cervicocarcinoma.

HEALTH PROBLEM: Cervical cancer is a disease which is highly preventable by means of Pap test screening for the precancerous lesions, which can be easily treated. Furthermore, in the near future, control of the disease will be enhanced by the vaccination which prevents the infection of those human papillomavirus types that cause the vast majority of cervical cancers. The effectiveness of screening in drastically reducing cervical cancer incidence has been clearly demonstrated. The epidemiology of cervical cancer in industrialised countries is now determined mostly by the Pap test coverage of the female population and by the ability of health systems to assure appropriate follow up after an abnormal Pap test. TECHNOLOGY DESCRIPTION: Today there are two fully automated systems for computer-assisted Pap test: the BD FocalPoint and the Hologic Imager. Recently, the Hologic Integrated Imager, a semi-automated system, was launched. The two fully automated systems are composed of a central scanner, where the machine examines the cytologic slide, and of one or more review stations, where the cytologists analyze the slides previously centrally scanned. The softwares used by the two systems identify the fields of interest so that the cytologists can look only at those points, automatically pointed out by the review station. Furthermore, the FocalPoint system classifies the slides according to their level of risk of containing signs of relevant lesions. Those in the upper classes--about one fifth of the slides--are labelled as « further review ¼, while those in the lower level of risk, i.e. slides that have such a low level of risk that they can be considered as negative with no human review, are labelled as « no further review ¼. The aim of computer-assisted Pap test is to reduce the time of slide examination and to increase productivity. Furthermore, the number of errors due to lack of attention may decrease. Both the systems can be applied to liquidbased cytology, while only the BD Focal Point can be used on conventional smears. BACKGROUND: Cytology screening has some critical points: there is a shortage of cytologists/cytotechnicians; the quality strongly depends on the experience and ability of the cytologist; there is a subjective component in the cytological diagnosis; in highly screened populations, the prevalence of lesions is very low and the activity of cytologists is very monotonous. On the other hand, a progressive shift to molecular screening using HPV-DNA test as primary screening test is very likely in the near future; cytology will be used as triage test, dramatically reducing the number of slides to process and increasing the prevalence of lesions in those Pap tests. OBJECTIVES: In this Report we assume that the diagnostic accuracy of computer-assisted Pap test is equal to the accuracy of manual Pap test and, consequently, that screening using computer-assisted Pap test has the same efficacy in reducing cervical cancer incidence and mortality. Under this assumption, the effectiveness/ benefit/utility is the same for the two screening modes, i.e. the economic analysis will be a cost minimization study. Furthermore, the screening process is identical for the two modalities in all the phases except for slide interpretation. The cost minimization analysis will be limited to the only phase differing between the two modes, i.e. the study will be a differential cost analysis between a labour-intensive strategy (traditional Pap test) and a technology-intensive strategy (the computer-assisted Pap test). Briefly, the objectives of this HTA Report are: to determine the break even point of computer-assisted Pap test systems, i.e. the volume of slides processed per year at which putting in place a computer-assisted Pap test system becomes economically convenient; to quantify the cost per Pap test in different scenarios according to screening centre activity volume, productivity of cytologist, type of cytology (conventional smear or liquid-based, fully automated or semi-automated computer-assisted); to analyse the computer-assisted Pap test in the Italian context, through a survey of the centres using the technology, collecting data useful for the sensitivity analysis of the economic evaluation; to evaluate the acceptability of the technology in the screening services; to evaluate the organizational and financial impact of the computer-assisted Pap test in different scenarios; to illustrate the ideal organization to implement computer-assisted Pap test in terms of volume of activity, productivity, and human and technological resources. PHASES OF THE ASSESSMENT: to produce this Report, the following process was adopted: application to the Ministry of health for a grant « Analysis of the impact of professional involvement in evidence generation for the HTA process ¼; within this project, the sub-project « Cost effectiveness evaluation of the computer-assisted Pap test in the Italian screening programmes ¼ was financed; constitution of the Working Group, which included the project coordinator, the principal investigator, and the health economist; identification of the centres using the computer-assisted Pap test and which had published scientific reports on the subject; identification of the Consulting Committee (stakeholder), which included screening programmes managers, pathologists, economists, health policy-makers, citizen organizations, and manufacturers. Once the evaluation was concluded, a plenary meeting with Working Group and Consulting Committee was held. The working group drafted the final version of this Report, which took into account the comments received. RESULTS AND CONCLUSIONS: the fully automated computer-assisted Pap test has an important financial and organizational impact on screening programmes. The assessment of this health technology reached the following conclusions: according to the survey results, after some distrust, cytologists accepted the use of the machine and appreciated the reduction in interpretation time and the reliability in identifying the fields of interest; from an economic point of view, the automated computer-assisted Pap test can be convenient only with conventional smears if the screening centre has a volume of more than 49,000 slides/year and the cytologist productivity increases about threefold. It must be highlighted that it is not sufficient to adopt the automated Pap test to reach such an increase in productivity; the laboratory must be organised or re-organised to optimise the use of the review stations and the person time. In the case of liquid-based cytology, the adoption of automated computer- assisted Pap test can only increase the costs. In fact, liquid-based cytology increases the cost of consumable materials but reduces the interpretation time, even in manual screening. Consequently, the reduction of human costs is smaller in the case of computer-assisted screening. Liquid-based cytology has other implications and advantages not linked to the use of computer-assisted Pap test that should be taken into account and are beyond the scope of this Report; given that the computer-assisted Pap test reduces human costs, it may be more advantageous where the cost of cytologists is higher; given the relatively small volume of activity of screening centres in Italy, computer-assisted Pap test may be reasonable for a network using only one central scanner and several remote review stations; the use of automated computer-assisted Pap test only for quality control in a single centre is not economically sustainable. In this case as well, several centres, for example at the regional level, may form a consortium to reach a reasonable number of slides to achieve the break even point. Regarding the use of a machine rather than human intelligence to interpret the slides, some ethical issues were initially raised, but both the scientific community and healthcare professionals have accepted this technology. The identification of fields of interest by the machine is highly reproducible, reducing subjectivity in the diagnostic process. The Hologic system always includes a check by the human eye, while the FocalPoint system identifies about one fifth of the slides as No Further Review. Several studies, some of which conducted in Italy, confirmed the reliability of this classification. There is still some resistance to accept the practice of No Further Review. A check of previous slides and clinical data can be useful to make the cytologist and the clinician more confident. RECOMMENDATIONS: Computer-assisted automated Pap test may be introduced only if there is a need to increase the volume of slides screened to cover the screening target population and sufficient human resources are not available. Switching a programme using conventional slides to automatic scanning can only lead to a reduction in costs if the volume of slides per year exceeds 49,000 slides/annum and cytologist productivity is optimised to more than 20,000 slides per year. At a productivity of 15,000 or fewer, the automated computer-assisted Pap test cannot be convenient. Switching from manual screening with conventional slides to automatic scanning with liquid-based cytology cannot generate any economic saving, but the system could increase output with a given number of staff. The transition from manual to computer assisted automated screening of liquid based cytology will not generate savings and the increase in productivity will be lower than that of the switch from manual/conventional to automated/conventional. The use of biologists or pathologists as cytologists is more costly than the use of cytoscreeners. Given that the automated computer-assisted Pap test reduces human resource costs, its adoption in a model using only biologists and pathologists for screening is more economically advantageous. (ABSTRACT TRUNCATED)

New markers of neonatal neurology.

Hypoxia-ischemia (H-I) constitutes the main phenomenon responsible for brain-blood barrier permeability modifications leading to cerebral vascular auto-regulation loss in newborns. Hypotension, cerebral ischemia, and reperfusion are the main events involved in vascular auto-regulation loss leading to cell death and tissue damage. Reperfusion could be critical since organ damage, particularly of the brain, may be amplified during this period. An exaggerated activation of vasoactive agents, of calcium mediated effects could be responsible for reperfusion injury (R-I), which, in turns, leads to cerebral hemorrhage and damage. These phenomena represent a common repertoire in newborns complicated by perinatal acute or chronic hypoxia treated by risky procedures such as mechanical ventilation, nitric oxide supplementation, brain cooling, and extracorporeal membrane oxygenation (ECMO). Despite accurate monitoring, the post-insult period is crucial, as clinical symptoms and standard monitoring parameters may be silent at a time when brain damage is already occurring and the therapeutic window for pharmacological intervention is limited. Therefore, the measurement of circulating biochemical markers of brain damage, such as vasoactive agents and nervous tissue peptides is eagerly awaited in clinical practice to detect high risk newborns. The present review is aimed at investigating the role of biochemical markers such as adrenomedullin, a vasoactive peptide; S100B, a calcium binding protein, activin A, a glycoprotein, in the cascade of events leading to I-R injury in newborns complicated by perinatal asphyxia.