Multi-centre randomised trial of invasive and less invasive surfactant delivery methods showed similar spirometry results at 5-9 years of age.

AIM: We explored whether subnormal forced expiratory volume within 1 s (FEV1 ) at 5-9 years of age was lower in children born preterm who received less invasive surfactant administration (LISA) rather than surfactant via an endotracheal tube. METHODS: The multi-centre, randomised Nonintubated Surfactant Application trial enrolled 211 preterm infants born at 23-26 weeks of gestation from 13 level III neonatal intensive care units from April 2009 to March 2012. They received surfactant via LISA (n = 107) or after conventional endotracheal intubation (n = 104). The follow-up assessments were carried out by a single team blinded to the group assignments. The main outcome was FEV1 < 80% of predicted values. RESULTS: Spirometry was successful in 102/121 children. The other children died or were lost to follow-up. Median FEV1 was 93% (interquartile range 80%-113%) of predicted values in the LISA group and 86% (interquartile range 77-102%) in the control group (p = 0.685). Rates of FEV1 < 80% were 11/57 (19%) and 15/45 (33%), respectively, which was an absolute risk reduction of 14% (95% confidence interval -3.1% to 31.2%, p = 0.235). There were no differences in other outcome measures. CONCLUSION: The proportion of children aged 5-9 years with subnormal FEV1 was not significantly different between the groups.

Developmental outcome of extremely preterm infants is improved after less invasive surfactant application: Developmental outcome after LISA.

AIM: The aim of this study was to evaluate neurocognitive outcome at 24 months of corrected age after less invasive surfactant application (LISA) in preterm infants born at 23-26 weeks of gestational age. METHODS: Surviving participants of a LISA trial conducted in 13 German level III neonatal intensive care units were reviewed for assessment of developmental outcome, hearing and vision problems, growth and rehospitalisation days. Maternal depression, breastfeeding rates and socio-economic factors were evaluated as potentially confounding factors. RESULTS: In total, 156/182 infants took part in the study, 78 had received surfactant via LISA and 78 via endotracheal intubation. 22% of LISA infants compared to 42% of intubated infants had a psychomotor development index (PDI) <70 (0.012). A significant difference in mental development index (MDI) was observed in the stratum of more mature infants (25 and 26 weeks of GA). For this group, MDI < 70 was observed in 4% of LISA infants vs 21% of intubated infants (P = 0.008). CONCLUSION: At 24 months of age, the LISA-treated infants scored less often PDI < 70 and had similar results in MDI. Infants born at 25 and 26 weeks treated with LISA had lower rates of severe disability. LISA is safe and may be superior.

Nonintubated Surfactant Application vs Conventional Therapy in Extremely Preterm Infants: A Randomized Clinical Trial.

IMPORTANCE: Treatment of respiratory distress syndrome in premature infants with continuous positive airway pressure (CPAP) preserves surfactant and keeps the lung open but is insufficient in severe surfactant deficiency. Traditional surfactant administration is related to short periods of positive pressure ventilation and implies the risk of lung injury. CPAP with surfactant but without any positive pressure ventilation may work synergistically. This randomized trial investigated a less invasive surfactant application protocol (LISA). OBJECTIVE: To test the hypothesis that LISA increases survival without bronchopulmonary dysplasia (BPD) at 36 weeks' gestational age in extremely preterm infants. DESIGN, SETTING, AND PARTICIPANTS: The Nonintubated Surfactant Application trial was a multicenter, randomized, clinical, parallel-group study conducted between April 15, 2009, and March 25, 2012, in 13 level III neonatal intensive care units in Germany. The final follow-up date was June 21, 2012. Participants included 211 of 558 eligible (37.8%) spontaneously breathing preterm infants born between 23.0 and 26.8 weeks' gestational age with signs of respiratory distress syndrome. In an intention-to-treat design, infants were randomly assigned to receive surfactant either via a thin endotracheal catheter during CPAP-assisted spontaneous breathing (intervention group) or after conventional endotracheal intubation during mechanical ventilation (control group). Analysis was conducted from September 6, 2012, to June 20, 2013. INTERVENTION: LISA via a thin catheter. MAIN OUTCOMES AND MEASURES: Survival without BPD at 36 weeks' gestational age. RESULTS: Of 211 infants who were randomized, 104 were randomized to the control group and 107 to the LISA group. Of the infants who received LISA, 72 (67.3%) survived without BPD compared with 61 (58.7%) of those in the control group. The reduction in absolute risk was 8.6% (95% CI, -5.0% to 21.9%; P = .20). Intervention group infants were less frequently intubated (80 infants [74.8%] vs 103 [99.0%]; P < .001) and required fewer days of mechanical ventilation. Significant reductions were seen in pneumothorax (5 of 105 intervention group infants [4.8%] vs 13 of 103 12.6%]; P = .04) and severe intraventricular hemorrhage (11 infants [10.3%] vs 23 [22.1%]; P = .02), and the combined survival without severe adverse events was increased in the intervention group (54 infants [50.5%] vs 37 [35.6%]; P = .02; absolute risk reduction, 14.9; 95% CI, 1.4 to 28.2). CONCLUSIONS AND RELEVANCE: LISA did not increase survival without BPD but was associated with increased survival without major complications. Because major complications are related to lifelong disabilities, LISA may be a promising therapy for extremely preterm infants. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN64011614.

Antioxidative status and oxidative stress in the fetal circulation at birth: the effects of time of delivery and presence of labor.

BACKGROUND: There are important physiological changes in the maternal, placental, and fetal compartments during pregnancy and labor. Increased oxidative stress has been demonstrated during labor. Melatonin has been reported to serve as an indirect antioxidant via the stimulation and induction of antioxidant enzymes as superoxide dismutase (SOD) and glutathione peroxidase (Gpx) in several tissues. AIM: : To assess whether the melatonin status, presence of labor at the time of birth and the time of delivery influence the extracellular antioxidative enzymes and DNA oxidative stress in newborns. METHODS: The extracellular antioxidative status and oxidative stress were analyzed by measuring the concentrations of the SOD3, Gpx3 and 8-hydroxydeoxyguanosine (8-OHdG) in the cord blood of 135 newborns. Newborns delivered during the day and at night and newborns delivered by spontaneous vaginal delivery (labor group) or elective caesarean section delivery (no labor group) were studied. OUTCOME MEASURES: The concentration of melatonin, SOD3, Gpx3 and 8-OHdG. RESULTS: Independent of the time of delivery, we found significantly higher melatonin, SOD3 and Gpx3 but lower 8-OHdG concentrations in the labor group than in the no labor group. We did not observe a correlation between the concentration of melatonin and SOD3, Gpx3 or 8-OHdG, or a day-night difference in SOD3, Gpx3 or 8-OHdG. CONCLUSION: Our findings suggest that oxidative stress during labor leads to an elevation of melatonin, SOD3 and Gpx3 in the fetal circulation, protecting the newborn from serious impairment, which is reflected by lower 8-OHdG levels. The melatonin status at the time of birth does not influence the extracellular SOD3 or Gpx3 concentrations.

Remifentanil-induced tolerance, withdrawal or hyperalgesia in infants: a randomized controlled trial. RAPIP trial: remifentanil-based analgesia and sedation of paediatric intensive care patients.

BACKGROUND: Short-acting opioids like remifentanil are suspected of an increased risk for tolerance, withdrawal and opioid-induced hyperalgesia (OIH). These potential adverse effects have never been investigated in neonates. OBJECTIVES: To compare remifentanil and fentanyl concerning the incidence of tolerance, withdrawal and OIH. METHODS: 23 mechanically ventilated infants received up to 96 h either a remifentanil- or fentanyl-based analgesia and sedation regimen with low-dose midazolam. We compared the required opioid doses and the number of opioid dose adjustments. Following extubation, withdrawal symptoms were assessed by a modification of the Finnegan score. OIH was evaluated by the CHIPPS scale and by testing the threshold of the flexion withdrawal reflex with calibrated von Frey filaments. RESULTS: Remifentanil had to be increased by 24% and fentanyl by 47% to keep the infants adequately sedated during mechanical ventilation. Following extubation, infants revealed no pronounced opioid withdrawal and low average Finnegan scores in both groups. Only 1 infant of the fentanyl group and 1 infant of the remifentanil group required methadone for treatment of withdrawal symptoms. Infants also revealed no signs of OIH and low CHIPPS scores in both groups. The median threshold of the flexion withdrawal reflex was 4.5 g (IQR = 2.3) in the fentanyl group and 2.7 g (IQR = 3.3) in the remifentanil group (p = 0.312), which is within the physiologic range of healthy infants. CONCLUSIONS: Remifentanil does not seem to be associated with an increased risk for tolerance, withdrawal or OIH.

Remifentanil/midazolam versus fentanyl/midazolam for analgesia and sedation of mechanically ventilated neonates and young infants: a randomized controlled trial.

PURPOSE: Common opioids for analgesia and sedation of mechanically ventilated infants may tend to accumulate and cause prolonged sedation with an unpredictable extubation time. Remifentanil is a promising option due to its unique pharmacokinetic properties, which seem to be valid in adults as well as in infants. METHODS: In this double-blind, randomized, controlled trial mechanically ventilated neonates and young infants (<60 days) received either a remifentanil or fentanyl-based analgesia and sedation regimen with low dose midazolam. The primary endpoint of the trial was the extubation time following discontinuation of the opioid infusion. Secondary endpoints included efficacy and safety aspects. RESULTS: Between November 2006 and March 2010, we screened 431 mechanically ventilated infants for eligibility. The intention to treat group included 23 infants who were assigned to receive either remifentanil (n = 11) or fentanyl (n = 12). Although this was designed as a pilot study, median extubation time was significantly shorter in the remifentanil group (80.0 min, IQR = 15.0-165.0) compared to the fentanyl group (782.5 min, IQR = 250.8-1,875.0) (p = 0.005). Remifentanil and fentanyl provided comparable efficacy with more than two-thirds of the measurements indicating optimal analgesia and sedation (66.4 and 70.2 %, respectively; p = 0.743). Overall, both groups had good hemodynamic stability and a comparably low incidence of adverse events. CONCLUSIONS: As neonates and young infants have a decreased metabolism of common opioids like fentanyl and are more prone to respiratory depression, remifentanil could be the ideal opioid for analgesia and sedation of mechanically ventilated infants.

Melatonin concentration in umbilical cord blood depends on mode of delivery.

BACKGROUND AND AIMS: Melatonin (MT) is rapidly transferred from the maternal to fetal circulation in humans. There is little knowledge about factors which influence the MT concentration (MTc) in the umbilical cord (UC) blood during delivery. The aim of our study was to evaluate the MT status in the UC blood according to the time and mode of delivery. SUBJECTS AND METHODS: Blood samples from umbilical artery (UA) and vein (UV) were collected from spontaneous vaginal deliveries (SVD, n=122) and cesarean section deliveries (CSD, n=188). MTc was measured using a commercially available radioimmunoassay. RESULTS: The MTc was not significantly different between UA and UV blood both at daytime and at nighttime (p=0.216 and p=0.440, respectively). Both in UA and in UV, the MTc was significantly higher at nighttime than at daytime (p<0.0001). Compared with the CSD group, MTc in the SVD group was significantly higher both at night- and daytime (p<0.05). MTc both in UA and in UV was found to be not significantly different between patients with and without risk factors for stress including pregnancy complications (e.g., preeclampsia) and intrapartum complications (e.g., emergency section, pathological doppler, and pathological cardiotocography) (p>0.05). CONCLUSION: Our study revealed for the first time that MTc both in UA and in UV depends on modus of labor. In agreement with other studies, we found a clear circadian MT rhythm in the UC blood of neonates. The results of our study may suggest to a physiological role of MT at the onset of labor.

Remifentanil degradation in umbilical cord blood of preterm infants.

BACKGROUND: No pharmacokinetic data about remifentanil in preterm infants exist, although remifentanil is increasingly used in this especially vulnerable subgroup of pediatric patients. Unfortunately, ethical restrictions in the volume of blood that can be withdrawn for kinetic sampling nearly prohibit pharmacokinetic studies in preterm infants. METHODS: Because remifentanil is rapidly metabolized by nonspecific blood esterases, we collected umbilical cord serum of preterm and term infants to investigate whether the activity of nonspecific blood esterases depends on gestational age. Umbilical cord serum, buffer solution, ascorbic acid, and remifentanil were mixed in a glass vial placed in a shaking water bath at 37°C. Subsequently, serum samples were subjected to liquid chromatography-mass spectrometry-based analysis of remifentanil and its metabolite GR90291 after 0, 30, 60, 100, and 150 min. RESULTS: We analyzed umbilical cord serum samples of 34 preterm infants (24-36 gestational weeks) and six term infants. The degradation rates of remifentanil to its major metabolite GR90291 were comparable in preterm and term infants. The overall median degradation half-life of remifentanil was 143 ± (interquartile range) 47 min (minimum, 76 min; maximum, 221 min) without significant differences between very preterm infants (less than 28 gestational weeks) and term infants. The remifentanil concentration remained stable in control runs without serum. CONCLUSIONS: Our study demonstrates that very preterm infants exhibit a high nonspecific esterase activity in umbilical cord blood that is comparable with that of term infants. These results support clinical experiences that remifentanil is rapidly metabolized by preterm infants without prolonged side effects.

CPAP combined with inhaled nitric oxide for treatment of lung hypoplasia and persistent foetal circulation due to prolonged PPROM.

BACKGROUND: Second trimester preterm premature rupture of the membranes (PPROM) before 24 weeks of gestation is associated with a high morbidity and mortality rate. AIM: To demonstrate the efficacy of early continuous positive airway pressure (CPAP) combined with inhaled nitric oxide (iNO) for treatment of preterm infants with lung hypoplasia and persistent foetal circulation (PFC) due to very early PPROM and prolonged severe oligohydramnios. METHODS: Seven infants with prolonged PPROM, lung hypoplasia, respiratory distress and persistent foetal circulation were intubated in the delivery room for subsequent surfactant and iNO application. As our new treatment strategy was to keep the period of mechanical ventilation as short as possible, all infants were switched on nasal CPAP combined with iNO within the first 24 hours. RESULTS: Mean gestational age at PPROM was 19+6 weeks (range 14+2 to 23+6 weeks) and the average latency period between rupture of membranes and delivery was 10+3 weeks (7+3 to 16+4 weeks). Infants were born at 30+3 weeks of gestation (28+3 to 33+1 weeks) with an average birth weight of 1468g (884 to 2200g). In all neonates CPAP combined with iNO reversed PFC and 6 patients stabilised without the need for reintubation and mechanical ventilation. One infant had to be reintubated following 12 hours of CPAP combined with iNO due to respiratory insufficiency. All seven infants survived to discharge. CONCLUSION: CPAP combined with iNO might be a promising approach for therapy of preterm infants with lung hypoplasia and persistent foetal circulation due to very early PPROM.

Remifentanil and propofol for weaning of mechanically ventilated pediatric intensive care patients.

Mechanically ventilated pediatric intensive care patients usually receive an analgesic and sedative to keep them comfortable and safe. However, common drugs like fentanyl and midazolam have a long context sensitive half time, resulting in prolonged sedation and an unpredictable extubation time. Children often awake slowly and struggle against the respirator, although their respiratory drive and their airway reflexes are not yet sufficient for extubation. In this pilot study, we replaced fentanyl and midazolam at the final phase of the weaning process with remifentanil and propofol. Twenty-three children aged 3 months-10 years were enrolled. Remifentanil and propofol revealed throughout excellent or good weaning conditions with rapid transition from hypnosis to the development of regular spontaneous breathing, airway protective reflexes, and an appropriate level of alertness. Extubation time following discontinuation of the remifentanil and propofol infusion was only 24 ± 20 min (5-80 min). We conclude that the combination of remifentanil and propofol is a promising option to improve the weaning conditions of pediatric intensive care patients. Randomized controlled trials are needed to compare remifentanil and propofol with conventional weaning protocols.

Propofol as an induction agent for endotracheal intubation can cause significant arterial hypotension in preterm neonates.

BACKGROUND: Propofol is gaining increasing popularity as induction agent for pediatric endotracheal intubation. Recently, propofol has been described for the first time as induction agent for endotracheal intubation in preterm neonates. Propofol seemed to be efficient, safe and ideally suited for the INSURE (Intubation SURfactant Extubation) procedure in preterm neonates. The purpose of this study was to document intubating conditions, vital signs, extubation times and outcome in preterm neonates receiving propofol as induction agent for the INSURE procedure. PATIENTS AND METHODS: Preterm neonates with a gestational age of 29-32 weeks and respiratory distress were eligible for INSURE with propofol if their postnatal age was <8 h. Exclusion criteria were any kind of disease not allowing early extubation. RESULTS: There were 13 inborn neonates enrolled for INSURE, mean gestational age was 30 weeks + 3 days, and mean birth weight was 1428 g (range 1170-1780 g). We stopped our observational study ahead of time as a result of significant cardiovascular side effects. Propofol generally offered good intubating conditions, but we encountered severe problems with arterial hypotension. A low propofol bolus of 1 mg kg(-1) caused a distinctive decline in mean arterial blood pressure from 38 mmHg (range 29-42 mmHg) prior premedication to 24 mmHg (22-40 mmHg) 10 min after propofol application. CONCLUSIONS: Our experience with propofol as induction agent for endotracheal intubation in preterm neonates reveals distinctive cardiovascular effects, which represent an important risk factor for serious complications of prematurity like intraventricular hemorrhage or periventricular leucomalacia. Propofol should be used with caution in very preterm neonates with respiratory distress during the first hours of life.

The anterior to midaxillary line between the 4th or 5th intercostal space (Buelau position) is safe for the use of thoracostomy tubes in preterm and term infants.

OBJECTIVES: Thoracostomy tubes are widely used in neonatology. Complications occurred significantly more frequently in infants, especially neonates, than in adults. Principally, the access is the modified Buelau position which takes place in the anterior axillary line at the 4th or 5th intercostal space above the margin of the ribs. AIM: This study seeks to determine the characteristics and topographic conditions of the anatomical structures at the ventral and lateral thoracic wall in the preterm and term neonate. BACKGROUND: Fifteen formalin-fixed stillborns were prepared (nine male, six female, 28-43 weeks gestational age). METHODS/MATERIALS: The anatomical preparation involved the complete thoracic wall region. RESULTS: In all preparations, a venous vessel was detected at the lateral wall and was identified as v. thoracoepigastrica without accompanying artery. Arteria (a.) and vena (v.) thoracica interna were regularly found close to the sternal plate on both sides between rib and fascia. With increasing gestational ages the course of the v. thoracoepigastrica varied significantly between the left and right thoracic wall. It was demonstrated that the v. thoracoepigastrica regularly arose within the abdominal or thoracic subcutaneous fat and drained into the v. subclavia. The variance between its course was almost 5-12 mm to the lateral or medial side. At both thoracic sides, no other organs or organ structures except lung parenchyma could be detected when using the Buelau position. CONCLUSIONS: The anterior to midaxillary line between the 4th or 5th intercostal space (Buelau position) is safe for the use of thoracostomy tubes in preterm and term infants.

Traumatic luxation of the nose in a newborn: case report and review of the literature.

During delivery the delicate structures of the face are predominantly exposed to external force effects and hence deformities on the nose can emerge as a birth-related trauma in newborns. As self-straightening of the nasal septum commonly occurs, a conservative therapy is recommended for most cases. We report on a case where a birth-related trauma of the nose leaded to acute breathing problems in a newborn with insufficient oxygenation. An overview about the available literature is given. A cautious reposition of the nose proved to be an appropriate management for short- and long-term development.

Early surfactant in spontaneously breathing with nCPAP in ELBW infants--a single centre four year experience.

OBJECTIVE: To evaluate whether the experience with a method to administer surfactant during spontaneous breathing with nasal continuous positive airway pressure (nCPAP) as primary respiratory support in infants with respiratory distress syndrome (RDS) influences the frequency of its use and affects the outcome of patients. METHODS: All inborn extremely low birthweight (ELBW) infants treated after introduction of the method were retrospectively studied (n=196). The entire observational period was divided into four periods (periods 1-4) and compared with a control period (period 0) (n=51). Primary respiratory support, demographics, prenatal risks and outcomes were compared. RESULTS: There were no changes in demographics or prenatal risks over time. The choice of nCPAP as initial airway management significantly increased from 69% to 91% and for nCPAP with surfactant from 75% to 86%. The rate of nCPAP failure decreased from 46% to 25%. Survival increased significantly between periods 0 and 1 from 76% to 90% and survival without bronchopulmonary dysplasia (BPD) rose from 65% to 80%. No changes in nonpulmonary outcomes were observed. CONCLUSION: The success of nCPAP increased with increasing use of nCPAP with surfactant. Simultaneously, mortality decreased without deterioration of other outcomes indicating that the use of surfactant in spontaneous breathing with nCPAP could be beneficial.

Consequences of Directive 2001/20/EC for investigator-initiated trials in the paediatric population--a field report.

On 4 April 2001, the European Parliament and Council enacted Directive 2001/20/EC, which had to be implemented in the national law of the European Union member states by May 2004. Its aim was to improve the quality of clinical trials and to assure the safety and well-being of trial subjects. We recently initiated the first paediatric investigator-initiated trial (IIT) at the University Hospital of Cologne according to Directive 2001/20/EC. This field report demonstrates the consequences and implications of the directive for paediatric IITs. Based on our experience, we agree that Directive 2001/20/EC improves the quality of clinical trials and assures the safety and well-being of trial subjects. However, at the same time, performing an IIT according to the new requirements is nearly impossible for clinicians and academic researchers without cooperating with expensive specialised experts, such as project managers, statisticians, data managers, pharmacists and monitors. Therefore, it is absolutely mandatory that financial support for paediatric IITs be adapted and increased in order to be able to meet the new requirements and obligations. Regulation (EC) No 141/2000 on orphan medicinal products and the recently adopted regulation on medicinal products for paediatric use (Paediatric Regulation) are important steps in improving clinical research in children. However, both regulations mainly encourage clinical research carried out by the pharmaceutical industry, whereas paediatric IITs are not in the scope of this legislation. We need to develop new concepts for funding to ensure future paediatric IITs, for example through specific grants from the European Union or member states.

Experience with remifentanil in neonates and infants.

Remifentanil is a relatively new synthetic opioid, which is not licensed worldwide for neonates and infants. Because of its unique pharmacokinetic properties with a short recovery profile, it could be the ideal opioid for neonates and infants, who are especially sensitive to respiratory depression by opioids. Therefore, we conducted a MEDLINE search on all articles dealing with the use of remifentanil in this important subgroup of patients. Most experience with remifentanil in neonates and infants is as maintenance anaesthesia during surgery. In approximately 300 neonates and infants, remifentanil proved to be an effective and safely used opioid for this indication. However, very limited data exist on remifentanil for analgesia and sedation of mechanically ventilated paediatric intensive care patients. Further research with remifentanil in neonates and infants should focus on this group of patients because remifentanil, with its very short context-sensitive half-life, could result in shorter extubation times compared with commonly used opioids such as morphine or fentanyl.