Physiological-based cord clamping in very preterm infants: the Aeration, Breathing, Clamping 3 (ABC3) trial-statistical analysis plan for a multicenter randomized controlled trial.

BACKGROUND: Mortality, cerebral injury, and necrotizing enterocolitis (NEC) are common complications of very preterm birth. An important risk factor for these complications is hemodynamic instability. Pre-clinical studies suggest that the timing of umbilical cord clamping affects hemodynamic stability during transition. Standard care is time-based cord clamping (TBCC), with clamping irrespective of lung aeration. It is unknown whether delaying cord clamping until lung aeration and ventilation have been established (physiological-based cord clamping, PBCC) is more beneficial. This document describes the statistical analyses for the ABC3 trial, which aims to assess the efficacy and safety of PBCC, compared to TBCC. METHODS: The ABC3 trial is a multicenter, randomized trial investigating PBCC (intervention) versus TBCC (control) in very preterm infants. The trial is ethically approved. Preterm infants born before 30 weeks of gestation are randomized after parental informed consent. The primary outcome is intact survival, defined as the composite of survival without major cerebral injury and/or NEC. Secondary short-term outcomes are co-morbidities and adverse events assessed during NICU admission, parental reported outcomes, and long-term neurodevelopmental outcomes assessed at a corrected age of 2 years. To test the hypothesis that PBCC increases intact survival, a logistic regression model will be estimated using generalized estimating equations (accounting for correlation between siblings and observations in the same center) with treatment and gestational age as predictors. This plan is written and submitted without knowledge of the data. DISCUSSION: The findings of this trial will provide evidence for future clinical guidelines on optimal cord clamping management at birth. TRIAL REGISTRATION: ClinicalTrials.gov NCT03808051. Registered on 17 January 2019.

Multicentre, randomised controlled trial of physiological-based cord clamping versus immediate cord clamping in infants with a congenital diaphragmatic hernia (PinC): statistical analysis plan.

BACKGROUND: Infants born with congenital diaphragmatic hernia (CDH) are at high risk of respiratory insufficiency and pulmonary hypertension. Routine practice includes immediate clamping of the umbilical cord and endotracheal intubation. Experimental animal studies suggest that clamping the umbilical cord guided by physiological changes and after the lungs have been aerated, named physiological-based cord clamping (PBCC), could enhance the fetal-to-neonatal transition in CDH. We describe the statistical analysis plan for the clinical trial evaluating the effects of PBCC versus immediate cord clamping on pulmonary hypertension in infants with CDH (PinC trial). DESIGN: The PinC trial is a multicentre, randomised controlled trial in infants with isolated left-sided CDH, born ≥ 35.0 weeks of gestation. The primary outcome is the incidence of pulmonary hypertension in the first 24 h after birth. Maternal outcomes include estimated maternal blood loss. Neonatal secondary outcomes include mortality before discharge, extracorporeal membrane oxygenation therapy, and number of days of mechanical ventilation. Infants are 1:1 randomised to either PBCC or immediate cord clamping using variable random permutated block sizes (4-8), stratified by treatment centre and estimated severity of pulmonary hypoplasia (i.e. mild/moderate/severe). At least 140 infants are needed to detect a relative reduction in pulmonary hypertension by one third, with 80% power and 0.05 significance level. A chi-square test will be used to evaluate the hypothesis that PBCC decreases the occurrence of pulmonary hypertension. This plan is written and submitted without knowledge of the collected data. The trial has been ethically approved. TRIAL REGISTRATION: ClinicalTrials.gov NCT04373902 (registered April 2020).

Sedation Prior to Intubation at Birth in Infants with Congenital Diaphragmatic Hernia: An International Survey on Current Practices.

INTRODUCTION: Infants with congenital diaphragmatic hernia (CDH) are commonly intubated immediately after birth. Consensus on whether to provide sedation prior to intubation in the delivery room is lacking, although avoidance of stress is especially important in this population with high risk of pulmonary hypertension. We aimed at obtaining an overview of local pharmacological interventions and at providing guidance on delivery room management. METHODS: An electronic survey was sent to international clinicians in referral centres for prenatal and postnatally diagnosed infants with CDH. This survey addressed demographic information, use of sedation and/or muscle relaxant prior to intubation, and use of pain scales in the delivery room. RESULTS: We received 93 relevant responses from 59 centres. Most centres were from Europe (n = 33, 56%), followed by North America (n = 16, 27%), Asia (n = 6, 10%), Australia (n = 2, 3%), and South America (n = 2, 3%). A total of 19% (11/59) of the centres routinely provided sedation prior to intubation in the delivery room, with midazolam and fentanyl being most often used. Methods of administration varied for all medications provided. Only 5 of 11 centres using sedation reported an adequate sedative effect prior to intubation. Muscle relaxants prior to intubation were used in 12% (7/59) of the centres, although not always in combination with sedation. CONCLUSION: This international survey shows a substantial variation in sedation practices in the delivery room and scarce use of both sedative agents and muscle relaxants prior to intubation of CDH infants. We provide guidance on developing protocols for pre-intubation medication in this population.

NEOnatal Central-venous Line Observational study on Thrombosis (NEOCLOT): evaluation of a national guideline on management of neonatal catheter-related venous thrombosis.

BACKGROUND: In critically ill (preterm) neonates, catheter-related venous thromboembolism (CVTE) can be a life-threatening complication. Evidence on optimal management in the literature is lacking. In the Netherlands, a consensus-based national management guideline was developed to create uniform CVTE management. OBJECTIVES: To evaluate the efficacy and safety of the national guideline. METHODS: This prospective, multicenter, observational study included all infants aged ≤6 months with CVTE in the Netherlands between 2014 and 2019. CVTE was divided into thrombosis in veins and that in the right atrium, with their own treatment algorithms. The primary outcomes were recurrent venous thrombotic events (VTEs) and/or death due to CVTE as well as major bleeding. RESULTS: Overall, 115 neonates were included (62% male; 79% preterm). The estimated incidence of CVTE was 4.0 per 1000 neonatal intensive care unit admissions. Recurrent thrombosis occurred in 2 (1.7%) infants and death due to CVTE in 1 (0.9%) infant. Major bleeding developed in 9 (7.8%) infants: 2 of 7 (29%) on recombinant tissue plasminogen activator, which was given for high-risk right-atrium thrombosis, and 7 of 63 (11%) on low-molecular-weight heparin (LMWH). Five of the 7 bleedings because of LMWH were complications of subcutaneous catheter use for LMWH administration. CONCLUSION: The management of neonatal CVTE according to the Dutch CVTE management guideline led to a low incidence of recurrent VTEs and death due to VTEs. Major bleeding occurred in 7.8% of the infants. Specific guideline adjustments may improve efficacy and, especially, safety of CVTE management in neonates.

The Oxygen Saturation Index as Early Predictor of Outcomes in Congenital Diaphragmatic Hernia.

OBJECTIVE: The aim of the study was to evaluate the oxygen saturation index (OSI) as an early predictor of clinical deterioration in infants with congenital diaphragmatic hernia (CDH). METHODS: A single-center retrospective cohort study was conducted in consecutive infants with isolated CDH with continuous OSI measurements collected in the first 24 h after birth between June 2017 and July 2021. Outcomes of interest were pulmonary hypertension, extracorporeal membrane oxygenation (ECMO)-therapy, and mortality. We evaluated the discriminative values of the maximum OSI value and of mean OSI values with receiver operator characteristic (ROC) analysis and the area under the ROC curve. RESULTS: In 42 infants with 49,473 OSI measurements, the median OSI was 5.0 (interquartile range 3.1-10.6). Twenty-seven infants developed pulmonary hypertension on a median of day 1 (1-1), of which 15 infants had an indication for ECMO-therapy, and 6 infants died. Maximum OSI values were associated with pulmonary hypertension, ECMO-therapy, and mortality. Mean OSI values had an acceptable discriminative ability for pulmonary hypertension and an excellent discriminative ability for ECMO-therapy and mortality. Although OSI measurements were not always present in the first hours after birth, we determined discriminative cut-offs for mean OSI values already in these first hours for pulmonary hypertension, the need for ECMO-therapy, and mortality. CONCLUSIONS: Continuous OSI evaluation is a promising modality to identify those infants at highest risk for clinical deterioration already in the first hours after birth. This provides an opportunity to tailor postnatal management based on the individual patient's needs.

Physiological-based cord clamping in very preterm infants: the Aeration, Breathing, Clamping 3 (ABC3) trial-study protocol for a multicentre randomised controlled trial.

BACKGROUND: International guidelines recommend delayed umbilical cord clamping (DCC) up to 1 min in preterm infants, unless the condition of the infant requires immediate resuscitation. However, clamping the cord prior to lung aeration may severely limit circulatory adaptation resulting in a reduction in cardiac output and hypoxia. Delaying cord clamping until lung aeration and ventilation have been established (physiological-based cord clamping, PBCC) allows for an adequately established pulmonary circulation and results in a more stable circulatory transition. The decline in cardiac output following time-based delayed cord clamping (TBCC) may thus be avoided. We hypothesise that PBCC, compared to TBCC, results in a more stable transition in very preterm infants, leading to improved clinical outcomes. The primary objective is to compare the effect of PBCC on intact survival with TBCC. METHODS: The Aeriation, Breathing, Clamping 3 (ABC3) trial is a multicentre randomised controlled clinical trial. In the interventional PBCC group, the umbilical cord is clamped after the infant is stabilised, defined as reaching heart rate > 100 bpm and SpO2 > 85% while using supplemental oxygen < 40%. In the control TBCC group, cord clamping is time based at 30-60 s. The primary outcome is survival without major cerebral and/or intestinal injury. Preterm infants born before 30 weeks of gestation are included after prenatal parental informed consent. The required sample size is 660 infants. DISCUSSION: The findings of this trial will provide evidence for future clinical guidelines on optimal cord clamping management in very preterm infants at birth. TRIAL REGISTRATION: ClinicalTrials.gov NCT03808051. First registered on January 17, 2019.

Spontaneous breathing approach in mild congenital diaphragmatic hernia: A resuscitation algorithm.

Background: Infants with a congenital diaphragmatic hernia (CDH) and expected mild pulmonary hypoplasia have an estimated survival rate of 90%. Current guidelines for delivery room management do not consider the individual patient's disease severity, but an individualized approach with spontaneous breathing instead of routine mechanical ventilation could be beneficial for the mildest cases. We developed a resuscitation algorithm for this individualized approach serving two purposes: improving the success rate by structuring the approach and providing a guideline for other centers. Methods: An initial algorithm was discussed with all local stakeholders. Afterwards, the resulting algorithm was refined using input from international experts. Results: Eligible CDH infants: left-sided defect, observed to expected lung-to-head ratio ≥50%, gestational age at birth ≥37.0 weeks, and no major associated structural or genetic abnormalities. To facilitate fetal-to-neonatal transition, we propose to start stabilization with non-invasive respiratory support and to adjust this individually. Conclusions: Infants with mild CDH might benefit from an individualized approach for neonatal resuscitation. Herein, we present an algorithm that could serve as guidance for centers implementing this.

Physiological-based cord clamping versus immediate cord clamping for infants born with a congenital diaphragmatic hernia (PinC): study protocol for a multicentre, randomised controlled trial.

INTRODUCTION: Pulmonary hypertension is a major determinant of postnatal survival in infants with a congenital diaphragmatic hernia (CDH). The current care during the perinatal stabilisation period in these infants might contribute to the development of pulmonary hypertension after birth-in particular umbilical cord clamping before lung aeration. An ovine model of diaphragmatic hernia demonstrated that cord clamping after lung aeration, called physiological-based cord clamping (PBCC), avoided the initial high pressures in the lung vasculature while maintaining adequate blood flow, thereby avoiding vascular remodelling and aggravation of pulmonary hypertension. We aim to investigate if the implementation of PBCC in the perinatal stabilisation period of infants born with a CDH could reduce the incidence of pulmonary hypertension in the first 24 hours after birth. METHODS AND ANALYSIS: We will perform a multicentre, randomised controlled trial in infants with an isolated left-sided CDH, born at ≥35.0 weeks. Before birth, infants will be randomised to either PBCC or immediate cord clamping, stratified by treatment centre and severity of pulmonary hypoplasia on antenatal ultrasound. PBCC will be performed using a purpose-built resuscitation trolley. Cord clamping will be performed when the infant is considered respiratory stable, defined as a heart rate >100 bpm, preductal oxygen saturation >85%, while using a fraction of inspired oxygen of <0.5. The primary outcome is pulmonary hypertension diagnosed in the first 24 hours after birth, based on clinical and echocardiographic parameters. Secondary outcomes include neonatal as well as maternal outcomes. ETHICS AND DISSEMINATION: Central ethical approval was obtained from the Medical Ethical Committee of the Erasmus MC, Rotterdam, The Netherlands (METC 2019-0414). Local ethical approval will be obtained by submitting the protocol to the regulatory bodies and local institutional review boards. TRIAL REGISTRATION NUMBER: NCT04373902.

Effect of breathing on venous return during delayed cord clamping: an observational study.

OBJECTIVE: To investigate the effect of spontaneous breathing on venous return in term infants during delayed cord clamping at birth. METHODS: Echocardiographic ultrasound recordings were obtained directly after birth in healthy term-born infants. A subcostal view was used to obtain an optimal view of the inferior vena cava (IVC) entering the right atrium, including both the ductus venosus (DV) and the hepatic vein (HV). Colour Doppler was used to assess flow direction and flow velocity. Recordings continued until the umbilical cord was clamped and were stored in digital format for offline analyses. RESULTS: Ultrasound recordings were obtained in 15 infants, with a median (IQR) gestational age of 39.6 (39.0-40.9) weeks and a birth weight of 3560 (3195-4205) g. Flow was observed to be antegrade in the DV and HV in 98% and 82% of inspirations, respectively, with flow velocity increasing in 74% of inspirations. Retrograde flow in the DV was observed sporadically and only occurred during expiration. Collapse of the IVC occurred during 58% of inspirations and all occurred caudal to the DV inlet (100%). CONCLUSION: Spontaneous breathing was associated with collapse of the IVC and increased antegrade DV and HV flow velocity during inspiration. Therefore, inspiration appears to preferentially direct blood flow from the DV into the right atrium. This indicates that inspiration could be a factor driving placental transfusion in infants.

Knowledge Gaps in the Fetal to Neonatal Transition of Infants With a Congenital Diaphragmatic Hernia.

Clinical research for infants born with a congenital diaphragmatic hernia (CDH) has until recently mainly focused on advances in prenatal and postnatal treatment. However, during the early perinatal transition period there are major physiological adaptations. For most infants these changes will happen uneventfully, but for CDH infants this marks the beginning of serious respiratory complications. In recent years, there is emerging evidence that the clinical management during the perinatal stabilization period in the delivery room may influence postnatal outcomes. Herein, we discuss major knowledge gaps and novel concepts that aim to optimize fetal to neonatal transition for infants with CDH. One such novel and interesting approach is performing resuscitation with an intact umbilical cord, the efficacy of this procedure is currently being investigated in several clinical trials. Furthermore, close evaluation of neonatal physiological parameters in the first 24 h of life might provide early clues concerning the severity of lung hypoplasia and the risk of adverse outcomes. We will provide an overview of trending concepts and discuss potential areas for future research.

Ductal Flow Ratio as Measure of Transition in Preterm Infants After Birth: A Pilot Study.

Background: Cardiovascular changes during the transition from intra- to extrauterine life, alters the pressure gradient across the ductus arteriosus (DA). DA flow ratio (R-L/L-R) has been suggested to reflect the infant's transitional status and could potentially predict neonatal outcomes after preterm birth. Aim: Determine whether DA flow ratio correlates with oxygenation parameters in preterm infants at 1 h after birth. Methods: Echocardiography was performed in preterm infants born <32 weeks gestational age (GA), as part of an ancillary study. DA flow was measured at 1 h after birth. DA flow ratio was correlated with FiO2, SpO2, and SpO2/FiO2 (SF) ratio. The DA flow ratio of infants receiving physiological-based cord clamping (PBCC) or time-based cord clamping (TBCC) were compared. Results: Measurements from 16 infants were analysed (median [IQR] GA 29 [27-30] weeks; birthweight 1,176 [951-1,409] grams). R-L DA shunting was 16 [17-27] ml/kg/min and L-R was 110 [81-124] ml/kg/min. The DA flow ratio was 0.18 [0.11-0.28], SpO2 94 [93-96]%, FiO2 was 23 [21-28]% and SF ratio 4.1 [3.3-4.5]. There was a moderate correlation between DA flow ratio and SpO2 [correlation coefficient (CC) -0.415; p = 0.110], FiO2 (CC 0.384; p = 0.142) and SF ratio (CC -0.356; p = 0.175). There were no differences in DA flow measurements between infants where PBBC or TBCC was performed. Conclusion: In this pilot study we observed a non-significant positive correlation between DA flow ratio at 1 h after birth and oxygenation parameters in preterm infants.

Implementation of Delayed Cord Clamping for 3 Min During Term Cesarean Sections Does Not Influence Maternal Blood Loss.

Background: To assess maternal safety outcomes after a local protocol adjustment to change the interval of cord clamping to 3 min after term cesarean section. Design, Setting, and Patients: A retrospective cohort study in a tertiary referral hospital (Erasmus MC, Rotterdam). We included pregnant women who gave birth at term after cesarean section. A cohort (Nov 2016-Oct 2017) prior to the protocol implementation was compared to a cohort after its implementation (Nov 2017-Nov 2018). The study population covered 789 women (n = 376 pre-cohort; n = 413 post-cohort). Interventions: Implementation of a local protocol changing the interval of cord clamping to 3 min in all term births. Main outcome measures: Primary outcomes were the estimated maternal blood loss and the occurrence of postpartum hemorrhage (blood loss >1,000 ml). Secondary outcomes included both maternal as well as neonatal outcomes. Results: Estimated maternal blood loss was not significantly different between the pre-cohort and post-cohort (400 mL [300-600] vs. 400 mL [300-600], p = 0.52). The incidence of postpartum hemorrhage (26 [6.9%] vs. 35 (8.5%), OR 1.24, 95% CI 0.73-2.11) and maternal blood transfusion (9 [2%] vs. 13 (3%), OR 1.33, 95% CI 0.56-3.14) were not different. Hemoglobin change was significantly higher in the post-cohort (-0.8 mmol/L [-1.3 to -0.5] vs. -0.9 mmol/L [-1.4 to -0.6], p = 0.01). In the post-cohort, neonatal hematocrit levels were higher (51 vs. 55%, p = 0.004) and need for phototherapy was increased (OR 1.95, 95% CI 0.99-3.84). Conclusion: Implementation of delayed cord clamping for 3 min in term cesarean sections was not associated with increased maternal bleeding complications.

A review of different resuscitation platforms during delayed cord clamping.

There is a large body of evidence demonstrating that delaying clamping of the umbilical cord provides benefits for term and preterm infants. These benefits include reductions in mortality in preterm infants and improved developmental scores at 4 years of age in term infants. However, non-breathing or non-vigorous infants at birth are excluded due to the perceived need for immediate resuscitation. Recent studies have demonstrated early physiological benefits in both human and animal models if resuscitation is performed with an intact cord, but this is still an active area of research. Given the large number of ongoing and planned trials, we have brought together an international group that have been intimately involved in the development or use of resuscitation equipment designed to be used while the cord is still intact. In this review, we will present the benefits and limitations of devices that have been developed or are in use. Published trials or ongoing studies using their respective devices will also be reviewed.

Perinatal stabilisation of infants born with congenital diaphragmatic hernia: a review of current concepts.

Congenital diaphragmatic hernia (CDH) is associated with high mortality rates and significant pulmonary morbidity, mainly due to disrupted lung development related to herniation of abdominal organs into the chest. Pulmonary hypertension is a major contributor to both mortality and morbidity, however, treatment modalities are limited. Novel prenatal and postnatal interventions, such as fetal surgery and medical treatments, are currently under investigation. Until now, the perinatal stabilisation period immediately after birth has been relatively overlooked, although optimising support in these early stages may be vital in improving outcomes. Moreover, physiological parameters obtained from the perinatal stabilisation period could serve as early predictors of adverse outcomes, thereby facilitating both prevention and early treatment of these conditions. In this review, we focus on the perinatal stabilisation period by discussing the current delivery room guidelines in infants born with CDH, the physiological changes occurring during the fetal-to-neonatal transition in CDH, novel delivery room strategies and early predictors of adverse outcomes. The combination of improvements in the perinatal stabilisation period and early prediction of adverse outcomes may mitigate the need for specific postnatal management strategies.

Physiological-based cord clamping in very preterm infants - Randomised controlled trial on effectiveness of stabilisation.

AIM: To test whether stabilising very preterm infants while performing physiological-based cord clamping (PBCC) is at least as effective as the standard approach of time-based delayed cord clamping (DCC). METHODS: A randomised controlled non-inferiority study was performed in two centres from May until November 2018, including preterm infants born below 32 weeks of gestational age. Infants were allocated to PBCC or standard DCC. Infants receiving PBCC were stabilised on a purpose-built resuscitation table with an intact umbilical cord. The cord was clamped when the infant had regular spontaneous breathing, heart rate ≥100 bpm and SpO2 >90% while using FiO2 <0.40. In infants receiving DCC, the cord was clamped at 30-60 seconds after birth before they were transferred to the standard resuscitation table for further treatment and stabilisation. Primary outcome was time to reach respiratory stability. RESULTS: Thirty-seven infants (mean gestational age 29 + 0 weeks) were included. Mean cord clamping time was 5:49 ±â€¯2:37 min in the PBCC (n = 20) and 1:02 ±â€¯0:30 min in the DCC group (n = 17). Infants receiving PBCC needed less time to reach respiratory stability (PBCC 5:54 ±â€¯2:27 min; DCC 7:07 ±â€¯2:54 min; mean difference corrected for gestational age -1:19 min, 95% CI [-3:04-0:27]), showing non-inferiority with the pre-defined limit of 1:15 min. No significant differences between the groups were found for maternal blood loss, postpartum haemorrhage, infant temperature at admission or short-term neonatal outcomes. CONCLUSION: Stabilisation of very preterm infants with physiological-based cord clamping is at least as effective as with standard DCC. CLINICAL TRIAL REGISTRATION: Netherlands Trial Register (NTR7194/NL7004).

Effectiveness of Stabilization of Preterm Infants With Intact Umbilical Cord Using a Purpose-Built Resuscitation Table-Study Protocol for a Randomized Controlled Trial.

Background: Most preterm infants fail to aerate their immature lungs at birth and need respiratory support for cardiopulmonary stabilization. Cord clamping before lung aeration compromises cardiovascular function. Delaying cord clamping until the lung has aerated may be beneficial for preterm infants by optimizing hemodynamic transition and placental transfusion. A new purpose-built resuscitation table (the Concord) has been designed making it possible to keep the cord intact after preterm birth until the lung is aerated and the infant is respiratory stable and breathing [Physiological-Based Cord Clamping (PBCC)]. The aim of this study is to test the hypothesis whether stabilizing preterm infants by PBCC is at least as effective as the standard approach using time-based Delayed Cord Clamping (DCC). Study design: This is a randomized controlled non-inferiority study including 64 preterm infants born at <32 weeks of gestation. Infants will be randomized to either the PBCC approach or standard DCC. In case of PBCC, infants will be stabilized with an intact umbilical cord and the cord will only be clamped when the infant is considered respiratory stable, defined as the establishment of regular spontaneous breathing, a heart rate ≥100 bpm and oxygen saturation above 90% while using inspired fraction of oxygen (FiO2) < 0.40. The Concord will be used, which allows giving respiratory support with an intact umbilical cord. In the DCC group infants are clamped first before they are transferred to the standard resuscitation table for further treatment and stabilization. Cord clamping is time-based and delayed at 30-60 s. The primary outcome will be the time to respiratory stability of the infant, starting from birth. Secondary outcomes will include details of stabilization, important clinical outcomes of prematurity and maternal safety outcomes. Discussion: We expect that PBCC using the Concord may reduce major morbidities and mortality in preterm infants. The current study protocol will assess the effectivity of stabilization. Once effectivity of stabilization is confirmed, we will start a large multicenter randomized clinical trial to investigate whether PBCC reduces mortality and morbidity in preterm infants compared to the standard approach. Trial registration: Netherlands Trial Registry NTR7194, registered on April 20th, 2018.

Physiological-based cord clamping in preterm infants using a new purpose-built resuscitation table: a feasibility study.

OBJECTIVE: Physiological-based cord clamping (PBCC) led to a more stable cardiovascular adaptation and better oxygenation in preterm lambs, but in preterm infants, this approach has been challenging. Our aim was to assess the feasibility of PBCC, including patterns of oxygen saturation (SpO2) and heart rate (HR) during stabilisation in preterm infants using a new purpose-built resuscitation table. DESIGN: Observational study. SETTING: Tertiary referral centre, Leiden University Medical Centre, The Netherlands. PATIENTS: Infants born below 35 weeks' gestational age. INTERVENTIONS: Infants were stabilised on a new purpose-built resuscitation table (Concord), provided with standard equipment needed for stabilisation. Cord clamping was performed when the infant was stable (HR >100 bpm, spontaneous breathing on continuous positive airway pressure with tidal volumes >4 mL/kg, SpO2 ≥25th percentile and fraction of inspired oxygen (FiO2) <0.4). RESULTS: Thirty-seven preterm infants were included; mean (SD) gestational age of 30.9 (2.4) weeks, birth weight 1580 (519) g. PBCC was successful in 33 infants (89.2%) and resulted in median (IQR) cord clamping time of 4:23 (3:00-5:11) min after birth. There were no maternal or neonatal adverse events. In 26/37 infants, measurements were adequate for analysis. HR was 113 (81-143) and 144 (129-155) bpm at 1 min and 5 min after birth. SpO2 levels were 58%(49%-60%) and 91%(80%-96%)%), while median FiO2 given was 0.30 (0.30-0.31) and 0.31 (0.25-0.97), respectively. CONCLUSION: PBCC in preterm infants using the Concord is feasible. HR remained stable, and SpO2 quickly increased with low levels of oxygen supply. TRIAL REGISTRATION NUMBER: NTR6095, results.

Clinical aspects of incorporating cord clamping into stabilisation of preterm infants.

Fetal to neonatal transition is characterised by major pulmonary and haemodynamic changes occurring in a short period of time. In the international neonatal resuscitation guidelines, comprehensive recommendations are available on supporting pulmonary transition and delaying clamping of the cord in preterm infants. Recent experimental studies demonstrated that the pulmonary and haemodynamic transition are intimately linked, could influence each other and that the timing of umbilical cord clamping should be incorporated into the respiratory stabilisation. We reviewed the current knowledge on how to incorporate cord clamping into stabilisation of preterm infants and the physiological-based cord clamping (PBCC) approach, with the infant's transitional status as key determinant of timing of cord clamping. This approach could result in optimal timing of cord clamping and has the potential to reduce major morbidities and mortality in preterm infants.

NEOnatal Central-venous Line Observational study on Thrombosis (NEOCLOT): evaluation of a national guideline on management of neonatal catheter-related thrombosis.

BACKGROUND: In critically ill (preterm) neonates, central venous catheters (CVCs) are increasingly used for administration of medication or parenteral nutrition. A serious complication, however, is the development of catheter-related thrombosis (CVC-thrombosis), which may resolve by itself or cause severe complications. Due to lack of evidence, management of neonatal CVC-thrombosis varies among neonatal intensive care units (NICUs). In the Netherlands an expert-based national management guideline has been developed which is implemented in all 10 NICUs in 2014. METHODS: The NEOCLOT study is a multicentre prospective observational cohort study, including 150 preterm and term infants (0-6 months) admitted to one of the 10 NICUs, developing CVC-thrombosis. Patient characteristics, thrombosis characteristics, risk factors, treatment strategies and outcome measures will be collected in a web-based database. Management of CVC-thrombosis will be performed as recommended in the protocol. Violations of the protocol will be noted. Primary outcome measures are a composite efficacy outcome consisting of death due to CVC-thrombosis and recurrent thrombosis, and a safety outcome consisting of the incidence of major bleedings during therapy. Secondary outcomes include individual components of primary efficacy outcome, clinically relevant non-major and minor bleedings and the frequency of risk factors, protocol variations, residual thrombosis and post thrombotic syndrome. DISCUSSION: The NEOCLOT study will evaluate the efficacy and safety of the new, national, neonatal CVC-thrombosis guideline. Furthermore, risk factors as well as long-term consequences of CVC-thrombosis will be analysed. TRIAL REGISTRATION: Trial registration: Nederlands Trial Register NTR4336 . Registered 24 December 2013.