Andrew W Gill

Delaying cord clamping until ventilation onset improves cardiovascular function at birth in preterm lambs

•  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.

Initiation of Resuscitation with High Tidal Volumes Causes Cerebral Hemodynamic Disturbance, Brain Inflammation and Injury in Preterm Lambs

Aims Preterm infants can be inadvertently exposed to high tidal volumes (VT) in the delivery room, causing lung inflammation and injury, but little is known about their effects on the brain. The aim of this study was to compare an initial 15 min of high VT resuscitation strategy to a less injurious resuscitation strategy on cerebral haemodynamics, inflammation and injury. Methods Preterm lambs at 126 d gestation were surgically instrumented prior to receiving resuscitation with either: 1) High VT targeting 10–12 mL/kg for the first 15 min (n = 6) or 2) a protective resuscitation strategy (Prot VT), consisting of prophylactic surfactant, a 20 s sustained inflation and a lower initial VT (7 mL/kg; n = 6). Both groups were subsequently ventilated with a VT 7 mL/kg. Blood gases, arterial pressures and carotid blood flows were recorded. Cerebral blood volume and oxygenation were assessed using near infrared spectroscopy. The brain was collected for biochemical and histologic assessment of inflammation, injury, vascular extravasation, hemorrhage and oxidative injury. Unventilated controls (UVC; n = 6) were used for comparison. Results High VT lambs had worse oxygenation and required greater ventilatory support than Prot VT lambs. High VT resulted in cerebral haemodynamic instability during the initial 15 min, adverse cerebral tissue oxygenation index and cerebral vasoparalysis. While both resuscitation strategies increased lung and brain inflammation and oxidative stress, High VT resuscitation significantly amplified the effect (p = 0.014 and p<0.001). Vascular extravasation was evident in the brains of 60% of High VT lambs, but not in UVC or Prot VT lambs. Conclusion High VT resulted in greater cerebral haemodynamic instability, increased brain inflammation, oxidative stress and vascular extravasation than a Prot VT strategy. The initiation of resuscitation targeting Prot VT may reduce the severity of brain injury in preterm neonates.

A randomised placebo-controlled trial of early treatment of the patent ductus arteriosus

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).

Cardiovascular transition at birth: a physiological sequence

The transition to newborn life at birth involves major cardiovascular changes that are triggered by lung aeration. These include a large increase in pulmonary blood flow (PBF), which is required for pulmonary gas exchange and to replace umbilical venous return as the source of preload for the left heart. Clamping the umbilical cord before PBF increases reduces venous return and preload for the left heart and thereby reduces cardiac output. Thus, if ventilation onset is delayed following cord clamping, the infant is at risk of superimposing an ischemic insult, due to low cardiac output, on top of an asphyxic insult. Much debate has centered on the timing of cord clamping at birth, focusing mainly on the potential for a time-dependent placental to infant blood transfusion. This has prompted recommendations for delayed cord clamping for a set time after birth in infants not requiring resuscitation. However, recent evidence indicates that ventilation onset before cord clamping mitigates the adverse cardiovascular consequences caused by immediate cord clamping. This indicates that the timing of cord clamping should be based on the infant’s physiology rather than an arbitrary period of time and that delayed cord clamping may be of greatest benefit to apneic infants.

Cardiovascular and pulmonary consequences of airway recruitment in preterm lambs.

Increases in positive end-expiratory pressure (PEEP) improve arterial oxygenation in preterm infants, but the effects on cardiopulmonary hemodynamics are understood poorly. We aimed to determine the effect of increased PEEP on cardiopulmonary hemodynamics and to compare measurements from indwelling flow probes with Doppler echocardiography. Preterm lambs (129 +/- 1 days) were ventilated initially with a tidal volume of 7 ml/kg and 4 cmH(2)O of PEEP. In ramp lambs (n = 7), PEEP was increased by 2-cmH(2)O increments to 10 cmH(2)O and then in decrements back to 4 cmH(2)O. PEEP was unchanged in controls (n = 6). Doppler echocardiographic flow measurements in the left pulmonary artery (LPA) and ductus arteriosus (DA) were correlated with flow probe measurements. Compared with controls, high PEEP reduced LPA flow from baseline (10-cmH(2)O PEEP: 43 +/- 8% vs. control: 83 +/- 21%; P = 0.029). High PEEP increased the proportion of right-to-left (R-L) shunting through the DA, with a trend to an increased oxygenation index compared with controls (oxygenation index: 44.5 +/- 13.5 at 10-cmH(2)O PEEP vs. 19.4 +/- 4.5 in controls; P = 0.07). Increasing PEEP decreased heart rate (17 beats/min; P = 0.03) and tended to lower systolic arterial pressure (5.0 mmHg; P = 0.052) compared with controls. Doppler echocardiography measurement of LPA flows correlated strongly with indwelling flow probe (r(2) = 0.73, P < 0.001), except during highly turbulent flows. Increases in PEEP have significant cardiopulmonary consequences in preterm lambs, including reduced LPA flow and increased R-L shunt through the DA. These changes are likely due to the concomitant increase in downstream pulmonary vascular resistance and increased cardiovascular constraint induced by PEEP.

Intrauterine inflammation causes pulmonary hypertension and cardiovascular sequelae in preterm lambs

Chorioamnionitis increases the risk and severity of persistent pulmonary hypertension of the newborn in preterm infants. Exposure of preterm fetal lambs to intra-amniotic (IA) lipopolysaccharide (LPS) induces chorioamnionitis, causes hypertrophy of pulmonary resistance arterioles, and alters expression of pulmonary vascular growth proteins. We investigated the cardiopulmonary and systemic hemodynamic consequences of IA LPS in preterm lambs. Pregnant ewes received IA injection of LPS (n=6) or saline (controls; n=8) at 122 days gestation, 7 days before exteriorization, instrumentation, and delivery of the fetus with pulmonary and systemic flow probes and catheters at 129 days gestation. Newborn lambs were ventilated, targeting a tidal volume of 6-7 ml/kg and a positive end-expiratory pressure (PEEP) of 4 cmH2O. At 30 min, all lambs underwent a PEEP challenge: PEEP was increased by 2 cmH2O at 10-min intervals to 10 cmH2O and then decreased similarly to 4 cmH2O. Ventilation parameters, arterial blood flows, and pressures were recorded in real-time for 90 min. LPS lambs had higher total protein in bronchoalveolar lavage fluid (P<0.002), increased medial thickness of arteriolar walls (P=0.013), and right ventricular hypertrophy (P=0.012). Compared with controls, LPS lambs had worse oxygenation (P<0.001), decreased pulmonary blood flow (P=0.05), and higher pulsatility index (P<0.001) and pulmonary (P<0.001) and systemic arterial pressures (P=0.005) than controls. Intra-amniotic LPS increased right-to-left shunting across the ductus arteriosus (P=0.018) and decreased left ventricular output (P<0.001). We conclude that inflammation and pulmonary remodeling induced by IA LPS adversely alters pulmonary hemodynamics with subsequent cardiovascular and systemic sequelae, which may predispose the preterm lamb to persistent pulmonary hypertension of the newborn.

Ventilation onset prior to umbilical cord clamping (physiological-based cord clamping) improves systemic and cerebral oxygenation in preterm lambs.

Background As measurement of arterial oxygen saturation (SpO2) is common in the delivery room, target SpO2 ranges allow clinicians to titrate oxygen therapy for preterm infants in order to achieve saturation levels similar to those seen in normal term infants in the first minutes of life. However, the influence of the onset of ventilation and the timing of cord clamping on systemic and cerebral oxygenation is not known. Aim We investigated whether the initiation of ventilation, prior to, or after umbilical cord clamping, altered systemic and cerebral oxygenation in preterm lambs. Methods Systemic and cerebral blood-flows, pressures and peripheral SpO2 and regional cerebral tissue oxygenation (SctO2) were measured continuously in apnoeic preterm lambs (126±1 day gestation). Positive pressure ventilation was initiated either 1) prior to umbilical cord clamping, or 2) after umbilical cord clamping. Lambs were monitored intensively prior to intervention, and for 10 minutes following umbilical cord clamping. Results Clamping the umbilical cord prior to ventilation resulted in a rapid decrease in SpO2 and SctO2, and an increase in arterial pressure, cerebral blood flow and cerebral oxygen extraction. Ventilation restored oxygenation and haemodynamics by 5–6 minutes. No such disturbances in peripheral or cerebral oxygenation and haemodynamics were observed when ventilation was initiated prior to cord clamping. Conclusion The establishment of ventilation prior to umbilical cord clamping facilitated a smooth transition to systemic and cerebral oxygenation following birth. SpO2 nomograms may need to be re-evaluated to reflect physiological management of preterm infants in the delivery room.

Delayed versus Immediate Cord Clamping in Preterm Infants

Background The preferred timing of umbilical‐cord clamping in preterm infants is unclear. Methods 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. Results 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. Conclusions 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.)

Respiratory support for premature neonates in the delivery room: effects on cardiovascular function and the development of brain injury

The transition to newborn life in preterm infants is complicated by immature cardiovascular and respiratory systems. Consequently, preterm infants often require respiratory support immediately after birth. Although aeration of the lung underpins the circulatory transition at birth, positive pressure ventilation can adversely affect cardiorespiratory function during this vulnerable period, reducing pulmonary blood flow and left ventricular output. Furthermore, pulmonary volutrauma is known to initiate pulmonary inflammatory responses, resulting in remote systemic involvement. This review focuses on the downstream consequences of positive pressure ventilation, in particular, interactions between cardiovascular output and the initiation of a systemic inflammatory cascade, on the immature brain. Recent studies have highlighted that positive pressure ventilation strategies are precursors of cerebral injury, probably mediated through cerebral blood flow instability. The presence of, or initiation of, an inflammatory cascade accentuates adverse cerebral blood flow, in addition to being a direct source of brain injury. Importantly, the degree of brain injury is dependent on the nature of the initial ventilation strategy used.

The timing of umbilical cord clamping at birth: physiological considerations

While it is now recognized that umbilical cord clamping (UCC) at birth is not necessarily an innocuous act, there is still much confusion concerning the potential benefits and harms of this common procedure. It is most commonly assumed that delaying UCC will automatically result in a time-dependent net placental-to-infant blood transfusion, irrespective of the infant’s physiological state. Whether or not this occurs, will likely depend on the infant’s physiological state and not on the amount of time that has elapsed between birth and umbilical cord clamping (UCC). However, we believe that this is an overly simplistic view of what can occur during delayed UCC and ignores the benefits associated with maintaining the infant’s venous return and cardiac output during transition. Recent experimental evidence and observations in humans have provided compelling evidence to demonstrate that time is not a major factor influencing placental-to-infant blood transfusion after birth. Indeed, there are many factors that influence blood flow in the umbilical vessels after birth, which depending on the dominating factors could potentially result in infant-to-placental blood transfusion. The most dominant factors that influence umbilical artery and venous blood flows after birth are lung aeration, spontaneous inspirations, crying and uterine contractions. It is still not entirely clear whether gravity differentially alters umbilical artery and venous flows, although the available data suggests that its influence, if present, is minimal. While there is much support for delaying UCC at birth, much of the debate has focused on a time-based approach, which we believe is misguided. While a time-based approach is much easier and convenient for the caregiver, ignoring the infant’s physiology during delayed UCC can potentially be counter-productive for the infant.