OBJECTIVES To document the incidence, timing, degree, and associations of systemic hypoperfusion in the preterm infant and to explore the temporal relation between low systemic blood flow and the development of intraventricular haemorrhage (IVH). STUDY DESIGN 126 babies born before 30 weeks' gestation (mean 27 weeks, mean body weight 991 g) were studied with Doppler echocardiography and cerebral ultrasound at 5, 12, 24, and 48 hours of age. Superior vena cava (SVC) flow was assessed by Doppler echocardiography as the primary measure of systemic blood flow returning from the upper body and brain. Other measures included colour Doppler diameters of ductal and atrial shunts, as well as Doppler assessment of shunt direction and velocity, and right and left ventricular outputs. Upper body vascular resistance was calculated from mean blood pressure and SVC flow. RESULTS SVC flow below the range recorded in well preterm babies was common in the first 24 hours (48 (38%) babies), becoming significantly less common by 48 hours (6 (5%) babies). These low flows were significantly associated with lower gestation, higher upper body vascular resistance, larger diameter ductal shunts, and higher mean airway pressure. Babies whose mothers had received antihypertensives had significantly higher SVC flow during the first 24 hours. Early IVH was already present in 9 babies at 5 hours of age. Normal SVC flows were seen in these babies except in 3 with IVH, which later extended, who all had SVC flow below the normal range at 5 and/or 12 hours. Eight of these 9 babies were delivered vaginally. Late IVH developed in 18 babies. 13 of 14 babies with grade 2 to 4 IVH had SVC flow below the normal range before development of an IVH. Two of 4 babies with grade 1 IVH also had SVC flow below the normal range before developing IVH, and the other 2 had SVC flow in the low normal range. In all, IVH was first seen after the SVC flow had improved, and the grade of IVH related significantly to the severity and duration of low SVC flow. The 9 babies who had SVC flow below the normal range and did not develop IVH or periventricular leucomalacia were considerably more mature (median gestation 28v 25 weeks). CONCLUSIONS Low SVC flow may result from an immature myocardium struggling to adapt to increased extrauterine vascular resistances. Critically low flow occurs when this is compounded by high mean airway pressure and large ductal shunts out of the systemic circulation. Late IVH is strongly associated with these low flow states and occurs as perfusion improves. Critically low superior vena cava flow occurs in a significant minority of very preterm infants These low flow states are poorly predicted by blood pressure This low flow is commonest in the first 12 to 24 hours, improving spontaneously after this time Late IVH is strongly associated with these low flow states and occurs as perfusion improves

Key points: Delayed cord clamping improves circulatory stability in preterm infants at birth, but the underlying reason is not known. In a new preterm lamb study we investigated whether delayed cord clamping until ventilation had been initiated improved pulmonary, cardiovascular and cerebral haemodynamic stability. We demonstrated that ventilation prior to cord clamping markedly improves cardiovascular function by increasing pulmonary blood flow before the cord is clamped, thus further stabilising the cerebral haemodynamic transition. These results show that delaying cord clamping until after ventilation onset leads to a smoother transition to newborn life, and probably underlies previously demonstrated benefits of delayed cord clamping. Abstract  Delayed cord clamping improves circulatory stability in preterm infants at birth, but the underlying physiology is unclear. We investigated the effects of umbilical cord clamping, before and after ventilation onset, on cardiovascular function at birth. Prenatal surgery was performed on lambs (123 days) to implant catheters into the pulmonary and carotid arteries and probes to measure pulmonary (PBF), carotid (CaBF) and ductus arteriosus blood flows. Lambs were delivered at 126 ± 1 days and: (1) the umbilical cord was clamped at delivery and ventilation was delayed for about 2 min (Clamp 1st; n = 6), and (2) umbilical cord clamping was delayed for 3–4 min, until after ventilation was established (Vent 1st; n = 6). All lambs were subsequently ventilated for 30 min. In Clamp 1st lambs, cord clamping rapidly (within four heartbeats), but transiently, increased pulmonary and carotid arterial pressures (by ∼30%) and CaBF (from 30.2 ± 5.6 to 40.1 ± 4.6 ml min⁻¹ kg⁻¹), which then decreased again within 30–60 s. Following ventilation onset, these parameters rapidly increased again. In Clamp 1st lambs, cord clamping reduced heart rate (by ∼40%) and right ventricular output (RVO; from 114.6 ± 14.4 to 38.8 ± 9.7 ml min⁻¹ kg⁻¹), which were restored by ventilation. In Vent 1st lambs, cord clamping reduced RVO from 153.5 ± 3.8 to 119.2 ± 10.6 ml min⁻¹ kg⁻¹, did not affect heart rates and resulted in stable blood flows and pressures during transition. Delaying cord clamping for 3–4 min until after ventilation is established improves cardiovascular function by increasing pulmonary blood flow before the cord is clamped. As a result, cardiac output remains stable, leading to a smoother cardiovascular transition throughout the early newborn period.

BACKGROUND Ventricular outputs cannot be used to assess systemic blood flow in preterm infants because they are confounded by shunts through the ductus arteriosus and atrial septum. However, flow measurements in the superior vena cava (SVC) can assess blood returning from the upper body and brain. OBJECTIVES To describe a Doppler echocardiographic technique that measures blood flow in the SVC, to test its reproducibility, and to establish normal ranges. DESIGN SVC flow was assessed together with right ventricular output and atrial or ductal shunting. Normal range was established in 14 infants born after 36 weeks' gestation (2 measurements taken in the first 48 hours) and 25 uncomplicated infants born before 30 weeks (4 measurements taken in the first 48 hours). Intra-observer and interobserver variability were tested in 20 preterm infants. RESULTS In 14 infants born after 36 weeks, median SVC flow rose from 76 ml/kg/min on day 1 to 93 ml/kg/min on day 2; in 25 uncomplicated very preterm infants, it rose from 62 ml/kg/min at 5 hours to 86 ml/kg/min at 48 hours. The lowest SVC flow for the preterm babies rose from 30 ml/kg/min at 5 hours to 46 ml/kg/min by 48 hours. Median intra-observer and interobserver variability were 8.1% and 14%, respectively. In preterm babies with a closed duct, SVC flow was a mean of 37% of left ventricular output and the two measures correlated significantly. CONCLUSIONS This technique can assess blood flow from the upper body, including the brain, in the crucial early postnatal period, and might allow more accurate assessment of the status of systemic blood flow and response to treatment. Superior vena cava flow offers a non-invasive means to assess systemic blood flow in newborn infants Superior vena cava flow increases over the first 48 hours in well term and preterm infants

The preferred timing of umbilical-cord clamping in preterm infants is unclear. We randomly assigned fetuses from women who were expected to deliver before 30 weeks of gestation to either immediate clamping of the umbilical cord (≤10 seconds after delivery) or delayed clamping (≥60 seconds after delivery). The primary composite outcome was death or major morbidity (defined as severe brain injury on postnatal ultrasonography, severe retinopathy of prematurity, necrotizing enterocolitis, or late-onset sepsis) by 36 weeks of postmenstrual age. Analyses were performed on an intention-to-treat basis, accounting for multiple births. Of 1634 fetuses that underwent randomization, 1566 were born alive before 30 weeks of gestation; of these, 782 were assigned to immediate cord clamping and 784 to delayed cord clamping. The median time between delivery and cord clamping was 5 seconds and 60 seconds in the respective groups. Complete data on the primary outcome were available for 1497 infants (95.6%). There was no significant difference in the incidence of the primary outcome between infants assigned to delayed clamping (37.0%) and those assigned to immediate clamping (37.2%) (relative risk, 1.00; 95% confidence interval, 0.88 to 1.13; P=0.96). The mortality was 6.4% in the delayed-clamping group and 9.0% in the immediate-clamping group (P=0.03 in unadjusted analyses; P=0.39 after post hoc adjustment for multiple secondary outcomes). There were no significant differences between the two groups in the incidences of chronic lung disease or other major morbidities. Among preterm infants, delayed cord clamping did not result in a lower incidence of the combined outcome of death or major morbidity at 36 weeks of gestation than immediate cord clamping. (Funded by the Australian National Health and Medical Research Council [NHMRC] and the NHMRC Clinical Trials Centre; APTS Australian and New Zealand Clinical Trials Registry number, ACTRN12610000633088.)

Objective Failure of closure of the patent ductus arteriosus (PDA) may be associated with harm. Early cardiac ultrasound-targeted treatment of a large PDA may result in a reduction in adverse outcomes and need for later PDA closure with no increase in adverse effects. Study design Multicentre, double-blind, placebo-controlled randomised trial. Setting Three neonatal intensive care units in Australia. Patients and interventions Eligible infants born <29 weeks were screened for a large PDA and received indomethacin or placebo before age 12 h. Main outcome Death or abnormal cranial ultrasound. Results The trial ceased enrolment early due to lack of availability of indomethacin. 164 eligible infants were screened before 12 h; of the 92 infants with a large PDA, 44 were randomised to indomethacin and 48 to placebo. There was no difference in the main outcome between groups. Infants receiving early indomethacin had significantly less early pulmonary haemorrhage (PH) (2% vs 21%), a trend towards less periventricular/intraventricular haemorrhage (PIVH) (4.5% vs 12.5%) and were less likely to receive later open-label treatment for a PDA (20% vs 40%). The 72 non-randomised infants with a small PDA were at low risk of pulmonary haemorrhage and had an 80% spontaneous PDA closure rate. Conclusions Early cardiac ultrasound-targeted treatment of a large PDA is feasible and safe, resulted in a reduction in early pulmonary haemorrhage and later medical treatment but had no effect on the primary outcome of death or abnormal cranial ultrasound. Registered Trial Australian New Zealand Clinical Trials Registry (ACTRN12608000295347).

AIM: To establish if there is an association between early cardiovascular adaptation and intraventricular haemorrhage (IVH). METHODS: One hundred and seventeen ventilated preterm infants (mean gestational age 27 weeks, mean birthweight 993 g) were studied echocardiographically within the first 36 hours. Measurements included right (RVO) and left ventricular outputs (LVO), ductus arteriosus (PDA) and atrial shunt diameter using colour Doppler and pulsed Doppler direction and velocity of both shunts. Clinical variables collected over the first 24 hours included use of antenatal steroids, respiratory severity, and mean blood pressure. Cerebral ultrasound scans were reported by a radiologist blinded to clinical and echocardiographic data. RESULTS: Antenatal steroids (two doses) had been given to 73% of the 86 infants with no IVH compared with 48% of the 21 infants with grades 1 and 2 IVH, and just 10% of 10 babies with grades 3 and 4 (P < 0.05). Both groups with IVH had significantly larger PDA diameters than the group with no IVH. Infants with grades 3 and 4 IVH had significantly lower RVO than the other infants. These differences were more pronounced when only infants with definite late IVH were analysed. Logistic regression analysis showed lack of antenatal steroids and larger PDA diameters were significantly associated with any grade of IVH and lack of antenatal steroids; lower RVO was significantly associated with grades 3 and 4 IVH. CONCLUSIONS: Larger early PDA shunts, lower RVO, and lack of antenatal steroids were significantly associated with IVH.