Comparison of "IN-REC-SUR-E" and LISA in preterm neonates with respiratory distress syndrome: a randomized controlled trial (IN-REC-LISA trial).

BACKGROUND: Surfactant is a well-established therapy for preterm neonates affected by respiratory distress syndrome (RDS). The goals of different methods of surfactant administration are to reduce the duration of mechanical ventilation and the severity of bronchopulmonary dysplasia (BPD); however, the optimal administration method remains unknown. This study compares the effectiveness of the INtubate-RECruit-SURfactant-Extubate (IN-REC-SUR-E) technique with the less-invasive surfactant administration (LISA) technique, in increasing BPD-free survival of preterm infants. This is an international unblinded multicenter randomized controlled study in which preterm infants will be randomized into two groups to receive IN-REC-SUR-E or LISA surfactant administration. METHODS: In this study, 382 infants born at 24+0-27+6 weeks' gestation, not intubated in the delivery room and failing nasal continuous positive airway pressure (nCPAP) or nasal intermittent positive pressure ventilation (NIPPV) during the first 24 h of life, will be randomized 1:1 to receive IN-REC-SUR-E or LISA surfactant administration. The primary outcome is a composite outcome of death or BPD at 36 weeks' postmenstrual age. The secondary outcomes are BPD at 36 weeks' postmenstrual age; death; pulse oximetry/fraction of inspired oxygen; severe intraventricular hemorrhage; pneumothorax; duration of respiratory support and oxygen therapy; pulmonary hemorrhage; patent ductus arteriosus undergoing treatment; percentage of infants receiving more doses of surfactant; periventricular leukomalacia, severe retinopathy of prematurity, necrotizing enterocolitis, sepsis; total in-hospital stay; systemic postnatal steroids; neurodevelopmental outcomes; and respiratory function testing at 24 months of age. Randomization will be centrally provided using both stratification and permuted blocks with random block sizes and block order. Stratification factors will include center and gestational age (24+0 to 25+6 weeks or 26+0 to 27+6 weeks). Analyses will be conducted in both intention-to-treat and per-protocol populations, utilizing a log-binomial regression model that corrects for stratification factors to estimate the adjusted relative risk (RR). DISCUSSION: This trial is designed to provide robust data on the best method of surfactant administration in spontaneously breathing preterm infants born at 24+0-27+6 weeks' gestation affected by RDS and failing nCPAP or NIPPV during the first 24 h of life, comparing IN-REC-SUR-E to LISA technique, in increasing BPD-free survival at 36 weeks' postmenstrual age of life. TRIAL REGISTRATION: ClinicalTrials.gov NCT05711966. Registered on February 3, 2023.

Serratia marcescens outbreak in a neonatal intensive care unit and the potential of whole-genome sequencing.

BACKGROUND: Serratia marcescens is notorious for its increasing antimicrobial resistance and potential to cause outbreaks in neonatal intensive care units (NICUs). A promising tool in outbreak investigations is whole-genome sequencing (WGS). OBJECTIVES: To describe a S. marcescens outbreak (2018-2019) in an NICU and discuss which infection control measures contributed to containment, addressing the potential of WGS. METHODS: S. marcescens isolates from patients and the environment isolated during the 2018-2019 NICU outbreak were analysed. In comparison, isolates from previous presumed NICU outbreaks and adult blood cultures were included. WGS and whole-genome multi-locus sequence typing analysis were performed. RESULTS: Sixty-three S. marcescens isolates were analysed. The 2018-2019 outbreak was divided into three clusters, including four environmental strains (drains, N=3; baby scale, N=1). The strains differed significantly from those of an NICU outbreak in 2014 and adult blood cultures. Besides standard infection control measures, the siphons were replaced and weekly decontamination was performed with acetic acid 10%. Seven acquired-resistance genes and 29 virulence-associated genes were detected. CONCLUSIONS: It was assumed that both neonates and drains were reservoirs of S. marcescens cross-contamination via the hands of healthcare workers and parents. Initially, standard measures, including hand hygiene, were reinforced. However, definitive containment was achieved only after replacement of the siphons and weekly decontamination with acetic acid. WGS enables faster recognition of an outbreak with accurate mapping of the spread, facilitating the implementation of infection control measures. WGS also provides interesting information about the spread of antibiotic resistance and virulence genes.

Characteristics of patients with atrial fibrillation prescribed edoxaban in Belgium and the Netherlands: insights from the ETNA-AF-Europe study.

BACKGROUND: Studies on the use of non-vitamin K antagonist oral anticoagulants in unselected patients with atrial fibrillation (AF) show that clinical characteristics and dosing practices differ per region, but lack data on edoxaban. METHODS: With data from Edoxaban Treatment in routiNe clinical prActice for patients with AF in Europe (ETNA-AF-Europe), a large prospective observational study, we compared clinical characteristics (including the dose reduction criteria for edoxaban: creatinine clearance 15-50 ml/min, weight ≤60 kg, and/or use of strong p­glycoprotein inhibitors) of patients from Belgium and the Netherlands (BeNe) with those from other European countries (OEC). RESULTS: Of all 13,639 patients in ETNA-AF-Europe, 2579 were from BeNe. BeNe patients were younger than OEC patients (mean age: 72.3 vs 73.9 years), and had lower CHA2DS2-VASc (mean: 2.8 vs 3.2) and HAS-BLED scores (mean: 2.4 vs 2.6). Patients from BeNe less often had hypertension (61.6% vs 80.4%), and/or diabetes mellitus (17.3% vs 23.1%) than patients from OEC. Moreover, relatively fewer patients in BeNe were prescribed the reduced dose of 30 mg edoxaban (14.8%) than in OEC (25.4%). Overall, edoxaban was dosed according to label in 83.1% of patients. Yet, 30 mg edoxaban was prescribed in the absence of any dose reduction criteria in 36.9% of 30 mg users (5.5% of all patients) in BeNe compared with 35.5% (9.0% of all patients) in OEC. CONCLUSION: There were several notable differences between BeNe and OEC regarding clinical characteristics and dosing practices in patients prescribed edoxaban, which are relevant for the local implementation of dose evaluation and optimisation. TRIAL REGISTRATION: NCT02944019; Date of registration 24 October 2016.

The search for novel treatment strategies for Streptococcus pneumoniae infections.

This review provides an overview of the most important novel treatment strategies against Streptococcus pneumoniae infections published over the past 10 years. The pneumococcus causes the majority of community-acquired bacterial pneumonia cases, and it is one of the prime pathogens in bacterial meningitis. Over the last 10 years, extensive research has been conducted to prevent severe pneumococcal infections, with a major focus on (i) boosting the host immune system and (ii) discovering novel antibacterials. Boosting the immune system can be done in two ways, either by actively modulating host immunity, mostly through administration of selective antibodies, or by interfering with pneumococcal virulence factors, thereby supporting the host immune system to effectively overcome an infection. While several of such experimental therapies are promising, few have evolved to clinical trials. The discovery of novel antibacterials is hampered by the high research and development costs versus the relatively low revenues for the pharmaceutical industry. Nevertheless, novel enzymatic assays and target-based drug design, allow the identification of targets and the development of novel molecules to effectively treat this life-threatening pathogen.

Surfactant use in late preterm infants: a survey among Belgian neonatologists.

Specific recommendations on surfactant administration in late preterm (LPT) infants with pulmonary disease are lacking. We performed an online-based, nationwide survey amongst all (n = 102) Belgian neonatologists to identify the use of surfactant in LPT infants suffering from several respiratory pathologies. The survey used clearly defined clinical cases and resulted in a 86% response rate. Neonatologists adhere to the 200 mg/kg initial surfactant dosing scheme. Surfactant is widely used in respiratory distress syndrome (70.1%), but there is less unanimity on its use in meconium aspiration syndrome (58.0%), transient tachypnoea of the newborn (30.6%), congenital pneumonia (27.2%) and congenital diaphragmatic hernia (8.6%). Respondents adhere to the European guideline of a timely referral to a newborn intensive care unit (non-invasive ventilation and FiO2 > 0.30 at 12 h of age), in order to minimise the risk of deterioration.Conclusion: We demonstrate a wide variety in the use of surfactant within LPT infants. The majority of Belgian neonatologists therefore urge for an investment in multi-centre trials on surfactant administration in LPT infants, in order to create an evidence-based practice as well as to reduce the strain on health care budgets.Trial registration: https://clinicaltrials.gov What is Known: • Any late preterm (LPT) infant with respiratory distress needs a timely referral to a neonatal intensive care unit in case of non-invasive ventilation and FiO2 > 0.30 at 12 h of life, in order to minimise the risk of acute deterioration as well as chronic lung disease. • Any modest increase in morbidity in the sizeable group of LPT infants exerts a significant strain on health care budgets. What is New: • We report the attitudes and opinions of Belgian neonatologists about the use of surfactant in LPT infants suffering from several respiratory diseases. • Our survey demonstrates a significant variability in practice between neonatologists during treatment of respiratory pathologies in LPT infants. This highlights an urgent need for univocal therapeutic lines.

Semiparametric estimation of structural failure time models in continuous-time processes.

Structural failure time models are causal models for estimating the effect of time-varying treatments on a survival outcome. G-estimation and artificial censoring have been proposed for estimating the model parameters in the presence of time-dependent confounding and administrative censoring. However, most existing methods require manually pre-processing data into regularly spaced data, which may invalidate the subsequent causal analysis. Moreover, the computation and inference are challenging due to the nonsmoothness of artificial censoring. We propose a class of continuous-time structural failure time models that respects the continuous-time nature of the underlying data processes. Under a martingale condition of no unmeasured confounding, we show that the model parameters are identifiable from a potentially infinite number of estimating equations. Using the semiparametric efficiency theory, we derive the first semiparametric doubly robust estimators, which are consistent if the model for the treatment process or the failure time model, but not necessarily both, is correctly specified. Moreover, we propose using inverse probability of censoring weighting to deal with dependent censoring. In contrast to artificial censoring, our weighting strategy does not introduce nonsmoothness in estimation and ensures that resampling methods can be used for inference.

Streptococcus pneumoniae galU gene mutation has a direct effect on biofilm growth, adherence and phagocytosis in vitro and pathogenicity in vivo.

Streptococcus pneumoniae, the most common cause of bacterial pneumonia, has developed a wide range of virulence factors to evade the immune system of which the polysaccharide capsule is the most important one. Formation of this capsule is dependent on the cps gene locus, but also involves other genes-like galU. The pyrophosphorylase encoded by galU plays a role in the UDP-glucose metabolism of prokaryotes and is required for the biosynthesis of capsular polysaccharides. In this paper, the effect of a galU mutation leading to a dysfunctional UDP-glucose pyrophosphorylase (UDPG:PP) on in vitro biofilm biomass, adherence to lung epithelial cells and macrophage phagocytosis is studied. Last, in vivo virulence using a Galleria mellonella model has been studied. We show that the mutation improves streptococcal adherence to epithelial cells and macrophage phagocytosis in vitro, while there is no definitive correlation on biofilm formation between parent and mutant strains. Moreover, in vivo virulence is attenuated for all mutated strains. Together, these results demonstrate that a galU mutation in S. pneumoniae influences host cell interactions in vitro and in vivo and can strongly influence the outcome of a streptococcal infection. As such, UDPG:PP is worth investigating further as a potential drug target.

Transplacental lidocaine intoxication.

Neonatal seizures are frequent in neonatal intensive care and the most common cause is perinatal asphyxia. Among other causes, toxin exposure is rare.We present a boy with an uneventful vaginal birth, who presented one hour after birth with apnea, hypotonia, mydriasis, tongue fasciculation, and tonic seizures. There was no hypoxic ischemic encephalopathy and brain imaging was normal. Toxicology screening revealed a toxic concentration of lidocaine in his blood. The intoxication was transplacental, as a cord blood sample confirmed the toxic level. This was probably due to maternal perineal nerve block with lidocaine.Perineal local infiltration of lidocaine is not without risk for the newborn. Toxicology screen remains an important tool in the work-up of neonatal seizures and sudden unexpected postnatal collapse.

Population Pharmacokinetics of Amoxicillin in Term Neonates Undergoing Moderate Hypothermia.

The pharmacokinetics (PK) of amoxicillin in asphyxiated newborns undergoing moderate hypothermia were quantified using prospective data (N = 125). The population PK was described by a 2-compartment model with a priori birthweight (BW) based allometric scaling. Significant correlations were observed between clearance (Cl) and postnatal age (PNA), gestational age (GA), body temperature (TEMP), and urine output (UO). For a typical patient with GA 40 weeks, BW 3,000 g, 2 days PNA (i.e., TEMP 33.5°C), and normal UO, Cl was 0.26 L/h (interindividual variability (IIV) 41.9%) and volume of distribution of the central compartment was 0.34 L/kg (IIV of 114.6%). For this patient, Cl increased to 0.41 L/h at PNA 5 days and TEMP 37.0°C. The respective contributions of both covariates were 23% and 27%. Based on Monte Carlo simulations we recommend 50 and 75 mg/kg/24h amoxicillin in three doses for patients with GA 36-37 and 38-42 weeks, respectively.

Inter-study variability of preclinical in vivo safety studies and translational exposure-QTc relationships--a PKPD meta-analysis.

BACKGROUND AND PURPOSE: Preclinical cardiovascular safety studies (CVS) have been compared between facilities with respect to their sensitivity to detect drug-induced QTc prolongation (ΔQTc). Little is known about the consistency of quantitative ΔQTc predictions that are relevant for translation to humans. EXPERIMENTAL APPROACH: We derived typical ΔQTc predictions at therapeutic exposure (ΔQTcTHER ) with 95% confidence intervals (95%CI) for 3 Kv 11.1 (hERG) channel blockers (moxifloxacin, dofetilide and sotalol) from a total of 14 CVS with variable designs in the conscious dog. Population pharmacokinetic-pharmacodynamic (PKPD) analysis of each study was followed by a meta-analysis (pooling 2-6 studies including 10-32 dogs per compound) to derive meta-predictions of typical ΔQTcTHER . Meta-predictions were used as a reference to evaluate the consistency of study predictions and to relate results to those found in the clinical literature. KEY RESULTS: The 95%CIs of study-predicted ΔQTcTHER comprised in 13 out of 14 cases the meta-prediction. Overall inter-study variability (mean deviation from meta-prediction at upper level of therapeutic exposure) was 30% (range: 1-69%). Meta-ΔQTcTHER predictions for moxifloxacin, dofetilide and sotalol overlapped with reported clinical QTc prolongation when expressed as %-prolongation from baseline. CONCLUSIONS AND IMPLICATIONS: Consistent exposure-ΔQTc predictions were obtained from single preclinical dog studies of highly variable designs by systematic PKPD analysis, which is suitable for translational purposes. The good preclinical-clinical pharmacodynamic correlations obtained suggest that such an analysis should be more routinely applied to increase the informative and predictive value of results obtained from animal experiments.

Exercise tolerance in obese vs. lean adolescents: a systematic review and meta-analysis.

To prescribe feasible and medically safe exercise interventions for obese adolescents, it remains to be determined whether exercise tolerance is altered and whether anomalous cardiopulmonary responses during maximal exercise testing are present. Studies that examined cardiopulmonary responses to maximal exercise testing in obese adolescents were searched: cardiopulmonary exercise tests with respiratory gas exchange measurements of peak oxygen uptake (VO2peak) were performed and comparisons between obese and lean adolescents were made. Study quality was assessed using a standardized item list. By meta-analyses VO2peak, peak cycling power output (Wpeak) and peak heart rate (HRpeak) were compared between groups. Nine articles were selected (333 obese vs. 145 lean adolescents). VO2peak (L min(-1)), HRpeak and Wpeak were not different between groups (P ≥ 0.10), while a trend was found for a reduced VO2peak (mL min(-1) kg(-1) lean tissue mass) (P=0.07) in obese vs. lean adolescents. It remained uncertain whether anomalous cardiopulmonary responses occur during maximal exercise testing in obese adolescents. In conclusion, a trend was found for lowered VO2peak (mL min(-1)kg(-1) lean tissue mass) in obese vs. lean adolescents. Whether cardiopulmonary anomalies during maximal exercise testing would occur in obese adolescents remains uncertain. Studies are therefore warranted to examine the cardiopulmonary response during maximal exercise testing in obese adolescents.

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 (CLD). Conventional IPPV is provided at 30-80 breaths per minute, while a newer form of ventilation called high frequency oscillatory ventilation (HFOV) provides 'breaths' at 10 - 15 cycles per second. This has been shown to result in less lung injury in experimental studies. OBJECTIVES: The objective of this review is to determine the effect of the elective use of high frequency oscillatory ventilation (HFOV) as compared to conventional ventilation (CV) in preterm infants who are mechanically ventilated for respiratory distress syndrome (RDS), on the incidence of chronic lung disease, mortality and other complications associated with prematurity and assisted ventilation. SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal hand searching by the Cochrane Collaboration, mainly in the English language. The search was updated in April 2007. SELECTION CRITERIA: Randomised controlled trials comparing HFOV and CV in preterm or low birth weight infants with pulmonary dysfunction, mainly due to RDS, who were given IPPV. Randomisation and commencement of treatment needed to be as soon as possible after the start of IPPV and usually in the first 12 hours of life. DATA COLLECTION AND ANALYSIS: The methodological quality of each trial was independently reviewed by the various authors. The standard effect measures are relative risk (RR) and risk difference (RD). From 1/RD the number needed to treat (NNT) to produce one outcome were calculated. For all measures of effect, 95% confidence intervals were used. In subgroup analyses the 99% CIs are also given for summary RRs in the text. Meta-analysis was performed using a fixed effects model. Where heterogeneity was over 50%, the random effects RR is also given. MAIN RESULTS: Fifteen eligible studies of 3,585 infants were included. Meta-analysis comparing HFOV with CV revealed no evidence of effect on mortality at 28 - 30 days of age or at approximately term equivalent age. These results were consistent across studies and in subgroup analyses. The effect of HFOV on CLD in survivors at term equivalent gestational age was inconsistent across studies and the reduction was of borderline significance overall. Subgroups of trials showed a significant reduction in CLD with HFOV when high volume strategy for HFOV was used, when piston oscillators were used for HFOV, when lung protective strategies for CV were not used, when randomisation occurred at two to six hours of age, and when inspiratory:expiratory ratio of 1:2 was used for HFOV. In the meta-analysis of all trials, pulmonary air leaks occurred more frequently in the HFOV group. In some studies, short-term neurological morbidity with HFOV was found, but this effect was not statistically significant overall. The subgroup of two trials not using a high volume strategy with HFOV found increased rates of Grade 3 or 4 intraventricular haemorrhage and of periventricular leukomalacia. An adverse effect of HFOV on long-term neurodevelopment was found in one large trial but not in the five other trials that reported this outcome. The rate of retinopathy of prematurity is reduced overall in the HFOV group. AUTHORS' CONCLUSIONS: There is no clear evidence that elective HFOV offers important advantages over CV when used as the initial ventilation strategy to treat preterm infants with acute pulmonary dysfunction. There may be a small reduction in the rate of CLD with HFOV use, but the evidence is weakened by the inconsistency of this effect across trials and the overall borderline significance. Future trials on elective HFOV should target those infants who are at most risk of CLD (extremely preterm infants), compare different strategies for generating HFOV and CV, and report important long-term neurodevelopmental outcomes.

[The Cochrane Collaboration and systematic literature reviews about the efficiency of a treatment]. / De cochrane collaboration en systematische literatuuroverzichten over de doeltreffendheid van een behandeling.

The Cochrane Collaboration is an international not-for-profit and independent organization, dedicated to making up-to-date, accurate information about the effects of healthcare readily available worldwide. It produces and disseminates systematic reviews of healthcare interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions. The Cochrane Collaboration was founded in 1993 and named after the British epidemiologist, Archie Cochrane. A Cochrane review is a systematic review. Those who prepare the reviews are mostly healthcare professionals who volunteer to work in one of the many Cochrane review groups, with editorial teams overseeing the preparation and maintenance of the reviews, as well as application of the rigorous quality standards for which Cochrane Reviews have become known. Based upon a clearly defined clinical question all steps of a scientific paper with a rigourous design are inside. This will guide the review process including strategies for locating and selecting studies critically appraising their relevance and validity and for analyzing variation among their results. If there are sufficient studies of good quality a meta-analysis can be performed. The major product of the Collaboration is the Cochrane Database of Systematic Reviews which is published quarterly as part of the Cochrane Library. From 2008 there will be also a place for systematic reviews of diagnostic accuracy studies. The Belgian Centre of Evidence-Based medicine, CEBAM, plays an important role as Belgian Branch of the Dutch Cochrane Collaboration in maintaining and promoting Cochrane Systematic Reviews.

[Medical end-of-life decisions in neonates and infants in Flanders, Belgium; 1999/2000]. / Medische beslissingen rond het levenseinde bij pasgeborenen en zuigelingen in Vlaanderen; 1991/'00.

OBJECTIVE: To determine the number of medical end-of-life decisions in critically ill neonates and infants in Flanders, Belgium. DESIGN: Retrospective. METHOD: A death certificate study on all deaths of neonates and infants in the whole of Flanders was carried out over a i2-month period (August 1999-July 2000). An anonymous questionnaire was sent by mail to the attending physician of each of the 292 children who died under the age of 1 year. All physicians who had attended at least one death during the study period were included in an attitude study. RESULTS: A total of 253 (87%) of the 292 questionnaires were returned and 121 (69%) of the 175 physicians involved completed the questions on attitude. An end-of-life decision had been possible in 194 (77%; 95% CI: 70.4-82.4) of the 253 deaths for which questionnaires were returned, and such a decision was actually made in 143 cases (57%; 95% CI: 48.9-64.0). Lethal drugs were administered in 15 of 117 early neonatal deaths and in 2 of 77 later deaths (13% versus 3%; p = 0.018). The attitude study showed that 69 (58%; 95% CI: 48.1-66.5) of the 120 physicians supported a change in the law making life-termination possible in some well-defined cases. CONCLUSION: The death of neonates and infants was commonly preceded by an end-of-life decision in Flanders. The type of decision varied substantially according to the age of the child. The majority of physicians involved, favoured legalization of the use of lethal drugs in some well-defined cases.

Neuromuscular paralysis for newborn infants receiving mechanical ventilation.

BACKGROUND: Ventilated newborn infants breathing in asynchrony with the ventilator are at risk for complications during mechanical ventilation, such as pneumothorax or intraventricular hemorrhage, and are exposed to more severe barotrauma, which consequently could impair their clinical outcome. Neuromuscular paralysis, which eliminates spontaneous breathing efforts of the infant, has potential advantages in this respect. However, a number of complications have been reported with muscle relaxation in infants, so that concerns exist regarding the safety of prolonged neuromuscular paralysis in newborn infants. OBJECTIVES: To determine whether routine neuromuscular paralysis of newborn infants receiving mechanical ventilation compared with no routine paralysis results in clinically important benefits or harms. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2004), MEDLINE (from 1966 to April 2004) and EMBASE (from 1988 to April 2004) were searched. References of review articles were hand searched. Language restriction was not imposed. SELECTION CRITERIA: All trials using random or quasi-random patient allocation, in which the routine use of neuromuscular blocking agents during mechanical ventilation was compared to no paralysis or selective paralysis in newborn infants. Methodological quality was assessed blindly and independently by the two authors. DATA COLLECTION AND ANALYSIS: Data were abstracted using standard methods of the Cochrane Collaboration and its Neonatal Review Group, with independent evaluation of trial quality, and abstraction and synthesis of data by both authors. Treatment effect was analysed using relative risk, risk difference and weighted mean difference. MAIN RESULTS: Ten possibly eligible trials were identified, of which six were included in the review. All the included trials studied preterm infants ventilated for respiratory distress syndrome, and used pancuronium as the neuromuscular blocking agent. In the analysis of the results of all trials, no significant difference was found in mortality, air leak or chronic lung disease, but there was a significant reduction in intraventricular hemorrhage and a trend towards less severe intraventricular hemorrhages. In the subgroup analysis of trials studying a selected population of ventilated infants with evidence of asynchronous respiratory efforts, a significant reduction in intraventricular hemorrhage (any grade and severe IVH) was found, and a trend towards less air leak. In the subgroup analysis of trials studying an unselected population of ventilated infants, no significant differences were found for any of the outcomes. AUTHORS' CONCLUSIONS: For ventilated preterm infants with evidence of asynchronous respiratory efforts, neuromuscular paralysis with pancuronium seems to have a favourable effect on intraventricular hemorrhage and possibly on air leak. Uncertainty remains, however, regarding the long term pulmonary and neurologic effects, and regarding the safety of prolonged use of pancuronium in ventilated newborn infants. There is no evidence from randomized trials on the effects of neuromuscular blocking agents other than pancuronium. The routine use of pancuronium or any other neuromuscular blocking agent in ventilated newborn infants cannot be recommended based on current evidence.

A classification of end-of-life decisions in neonates and infants.

AIM: Valid and reliable data are needed to gain insight into the decisions of paediatricians concerning the end of life of newborns and infants. Such data could throw light on the poorly documented aspects of medical practice regarding these end-of-life decisions (ELDs). In this article a classification of ELDs is developed. METHODS: The classification is developed from knowledge generated from large-scale epidemiological studies on ELDs. RESULTS: This classification sets out from considerations of the various possible medical end-of-life procedures for newborns and infants and from important ethical aspects of the decision-making process. From both ethical and legal viewpoints the life-shortening intention of the physician is a significant factor for the qualification of ELDs. Furthermore, the consultation of the parents is an important factor in absence of the possibility of the patient's self-determination. CONCLUSION: This classification has been devised with the aim of making reliable and valid descriptions of both the incidence and nature of ELDs in this specific population of newborns and infants.

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 intermittent positive pressure ventilation (IPPV) saves lives, lung distortion during its use is associated with lung injury and chronic lung disease (CLD). Conventional IPPV is provided at 30-80 breaths per minute while a newer form of ventilation called high frequency oscillatory ventilation (HFOV) provides 'breaths' at 10-15 cycles per second. This has been shown to result in less lung injury in experimental studies. OBJECTIVES: The objective of this review is to determine whether the elective use of high frequency oscillatory ventilation as compared to conventional ventilation (CV) in preterm infants who are mechanically ventilated for the respiratory distress syndrome decreases the incidence of chronic lung disease, without adverse effects. SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal hand searching by the Cochrane Collaboration, mainly in the English language. The search was updated in May 2003. SELECTION CRITERIA: Randomized controlled trials comparing HFOV and CV in preterm or low birth weight infants with pulmonary dysfunction, mainly due to RDS, who are to be given IPPV. Randomization and commencement of treatment should have been as soon as possible after the start of IPPV and usually in the first 12 hours of life. DATA COLLECTION AND ANALYSIS: The methodological quality of each trial was independently reviewed by the various authors. Each author extracted data separately; they were compared and differences were resolved. Treatment effects were expressed using relative risk (RR) and risk difference (RD). From 1/RD the number needed to treat (NNT) to produce one outcome were calculated. Ninety five percent confidence intervals were used for all measures of effect. MAIN RESULTS: Eleven eligible studies on 3,275 infants were included. Meta-analysis comparing HFOV with CV revealed no evidence of effect on mortality at 28-30 days of age or at approximately term equivalent age. These results were consistent across studies. The effect of HFOV on CLD in survivors at term equivalent GA was inconsistent across studies and not significant overall. Pre-specified subgroup analyses according to use of a high volume strategy, or use of surfactant, did not identify subgroups in which there was evidence of effect on death, or in which the size of effect on CLD was substantially increased, or in which heterogeneity of treatment effect on CLD was removed. Short term neurological morbidity caused by HFOV was found in some studies, but this effect was not statistically significant overall. The subgroup of two trials not using a high volume strategy with HFOV found increased rates of Grade 3 or 4 IVH and of periventricular leukomalacia. An adverse effect of HFOV on longer term neurodevelopment was found in one large trial but not in two other small trials which reported this outcome. REVIEWER'S CONCLUSIONS: There is no clear evidence from this systematic review that elective HFOV, as compared with CV, offers important advantages when used as the initial ventilation strategy to treat preterm babies with acute pulmonary dysfunction. There is no evidence of a reduction in death rate. There may be a small reduction in the rate of CLD with HFOV use but the evidence is weakened by the inconsistency of this effect across trials and is not significant overall. Adverse effects on short term neurological outcomes have been observed in some studies but these effects are not significant overall. Information about effects on long term outcome is not adequate overall. Any future trials on elective HFOV should target those infants who are at most risk of CLD (extremely preterm), compare different strategies for generating HFOV and CV, and report important long term pulmonary and neurodevelopmental outcomes. Economic analysis should also be incorporated.

Stability of far field R wave signals in different conditions.

AIMS: The presence of far field R wave sensing (FFRS) is usually evaluated in patients with dual chamber pacemakers in supine position. To check if this approach is valid, we tested whether FFRS is consistent both in terms of amplitude threshold and timing characteristics in different daily life conditions. METHODS AND RESULTS: In 42 patients with a DDD pacemaker, the presence, amplitude threshold and timing parameters of FFRS were therefore determined, with patients supine, standing and at peak exercise. Measurements were made of paced and sensed R waves, in unipolar and bipolar sensing configurations (at peak exercise only paced R waves and bipolar sensing). After paced R waves (bipolar sensing) amplitude thresholds/time of FFRS after V pace were 0.32+/-0.18 mV/119-139 ms (supine), 0.32+/-0.16 mV/114-130 ms (upright) and 0.27+/-0.13 mV/121-136 ms (exercise) - with unipolar sensing, this was 0.49+/-0.27 mV/101-150 ms (supine), 0.51+/-0.29 mV/100-144 ms (upright). After sensed R waves (bipolar sensing) amplitude thresholds/time of FFRS after V sense were 0.27+/-0.18 mV/24-42 ms (supine), 0.29+/-0.16 mV/18 to 41 ms (upright) - with unipolar sensing, thresholds were 0.59+/-0.32 mV/3-50 ms (supine), 0.59+/-0.36 mV/2-58 ms (upright). CONCLUSION: given the lower FFRS thresholds with bipolar sensing, bipolar sensing is superior in avoiding FFRS compared with unipolar sensing. No differences were found in terms of amplitude thresholds and timing characteristics with patients supine, standing and at peak exercise. Thus, measurements made in the supine position are basically sufficient to predict the presence/absence of FFRS under different conditions.

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 intermittent positive pressure ventilation (IPPV) saves lives, lung distortion during its use is associated with lung injury and chronic lung disease (CLD). Conventional IPPV is provided at 30-80 breaths per minute while a newer form of ventilation called high frequency oscillatory ventilation (HFOV) provides 'breaths' at 10-15 cycles per second. This has been shown to result in less lung injury in experimental studies. OBJECTIVES: The objective of this review is to determine whether the elective use of high frequency oscillatory ventilation as compared to conventional ventilation (CV) in preterm infants who are mechanically ventilated for the respiratory distress syndrome decreases the incidence of chronic lung disease, without adverse effects. SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal hand searching by the Cochrane Collaboration, mainly in the English language. The search was updated in October 2002. SELECTION CRITERIA: Randomized controlled trials comparing HFOV and CV in preterm or low birth weight infants with pulmonary dysfunction, mainly due to RDS, who are to be given IPPV. Randomization and commencement of treatment should have been as soon as possible after the start of IPPV and usually in the first 12 hours of life. DATA COLLECTION AND ANALYSIS: The methodological quality of each trial was independently reviewed by the various authors. Each author extracted data separately; they were compared and differences were resolved. Treatment effects were expressed using relative risk (RR) and risk difference (RD). From 1/RD the number needed to treat (NNT) for benefits, and number needed to harm (NNH) for adverse effects, were calculated. 95% confidence intervals were used. MAIN RESULTS: Meta-analysis of the ten eligible studies comparing HFOV with CV revealed no evidence of effect on mortality at 28-30 days of age or at approximately term equivalent age. These results were consistent across studies. HFOV caused a significant reduction in CLD in survivors at term equivalent GA. However, the effect was not large in absolute terms [NNT 17 (10, 50)], and was inconsistent across studies. HFOV caused a significant reduction in the aggregated outcome, death or CLD at term equivalent GA. Again, however, the effect was not large [(NNT 20 (11, 100)] and was not consistent across studies. Pre-specified subgroup analyses according to use of a high volume strategy, or use of surfactant, did not identify subgroups in which there was evidence of effect on death, or in which the size of effect on CLD was substantially increased, or in which heterogeneity of treatment effect on CLD was removed. Short term neurological morbidity caused by HFOV was found in some studies, but this effect was not statistically significant overall. The subgroup of two trials not using a high volume strategy with HFOV found increased rates of Grade 3 or 4 IVH and of periventricular leukomalacia. An adverse effect of HFOV on longer term neurodevelopment was found in one large trial but not in two other small trials which reported this outcome. REVIEWER'S CONCLUSIONS: There is strong evidence that HFOV had no significant effect on death as this result was consistent across trials. Although HFOV caused a modest reduction in CLD, this evidence is weaker, because of inconsistencies across trials in this effect. In general, subgroup analyses according to use of high volume strategy, or surfactant, did not remove this heterogeneity, which therefore remains largely unexplained. Any future trials on elective HFOV should target those infants who are at most risk of CLD (extremely preterm), compare different strategies for generating HFOV and report important long term pulmonary and neurodevelopmental outcomes. Economic analysis should also be incorporated.

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 intermittent positive pressure ventilation (IPPV) saves lives, lung distortion during its use is associated with lung injury and chronic lung disease (CLD). Conventional IPPV is provided at 30-80 breaths per minute while a newer form of ventilation called high frequency oscillatory ventilation (HFOV) provides 'breaths' at 10-15 cycles per second. This has been shown to result in less lung injury in experimental studies. OBJECTIVES: The objective of this review is to determine whether the elective use of high frequency oscillatory ventilation (HFOV) as compared to conventional ventilation (CV) in preterm infants who are mechanically ventilated for the respiratory distress syndrome decreases the incidence of chronic lung disease (CLD) without adverse effects. SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal hand searching by the Cochrane Collaboration, mainly in the English language. SELECTION CRITERIA: Randomized controlled trials comparing HFOV and CV in preterm or low birth weight infants with pulmonary dysfunction, mainly due to RDS, who are to be given IPPV. Randomization and commencement of treatment should have been as soon as possible after the start of IPPV and usually in the first 12 hours of life. DATA COLLECTION AND ANALYSIS: The methodological quality of each trial was independently reviewed by the various authors. Each author extracted data separately; they were compared and differences were resolved. The standard method of the Cochrane Neonatal Review Group was used to synthesize the data using relative risk (RR) and risk difference (RD). From 1/RD the number needed to treat (NNT) for benefits, and number needed to harm (NNH) for adverse effects, were calculated. 95% confidence intervals were used. MAIN RESULTS: Meta-analysis of the eight eligible studies comparing HFOV with CV revealed that there is no difference in mortality. There are trends toward decreases in CLD in survivors at 28-30 days, 'death or CLD at 28-30 days' and a significant reduction in CLD in survivors at 36-37 weeks postmenstrual age or discharge in the HFOV group (six trials, summary RR 0.73 (0.57, 0.93). There is a significant increase in severe (grades 3 & 4) intraventricular hemorrhage (IVH) and in any pulmonary air leak syndrome [summary RR 1.19 (1.03, 1.38)] in the HFOV group. Only 2 trials have included neurodevelopmental follow up and more survivors in the HFOV group are abnormal [summary RR 1.26 (1.01, 1.58)]. In the subgroup of six trials where a high volume strategy (HVS) was used for HFOV, this is associated with significantly lower rates of CLD in survivors at 28-30 days [three trials, summary RR 0.53 (0.36, 0.76)], of 'death or CLD at 28-30 days' [three trials, summary RR 0.56 (0.40, 0.77) and oxygen use at 36-37 weeks postmenstrual age or discharge [five trials, summary RR 0.72 (0.56, 0.93)]. There were no overall differences in the rates of IVH or PVL. One trial suggests that HFOV may reduce the cost of in-hospital care. In this group of trials HFOV is associated with a strong trend for an increased rate of gross pulmonary ALS (four trials, summary RR 1.54 (0.98, 2.42)] In the subgroup of two trials (HIFI 1989, Rettwitz-Volk 1998) not using a HVS there is no effect of HFOV on the rate of CLD; however, there is an increase in the rate of periventricular leukomalacia (PVL) [summary RR 1.64 (1.02, 2.64). REVIEWER'S CONCLUSIONS: Benefits of HFOV in terms of CLD appear to be outweighed by concerns about increased rates of pulmonary air leak and severe IVH. Until these issues are resolved HFOV cannot be recommended as the routine method of giving mechanical ventilation to preterm infants with RDS. Future trials should target very preterm infants who are at most risk of CLD and infants should be randomized in gestational age strata. Important long term pulmonary and neurodevelopmental outcomes should be measured and reported. Economic effects should be assessed.