Hemodynamic assessment of the patent ductus arteriosus: Beyond ultrasound.

Assessment and management of a patent ductus arteriosus (PDA) in premature infants remains problematic. The more immature the infant, the more likely a PDA is to be present, due to lower spontaneous PDA closure rates. Clinicians now recognize that not all PDAs require treatment and that selection of the group of infants with a more hemodynamically relevant PDA, often manifesting as an increasing systemic-to-pulmonary shunt, is increasingly important. Ultrasound is the mainstay of diagnosis and physiological assessment of the PDA; however, there are other methodologies used to assess hemodynamic importance of the PDA. These range from assessment of clinical signs through biomarkers and finally to physiological assessment of the end-organ effect of the PDA, using methods such as cerebral Doppler or near infra-red spectroscopy. Extended assessment of a PDA's physiological effect may lead to a more individualized approach to PDA treatment.

Role of neonatologist-performed echocardiography in the assessment and management of patent ductus arteriosus physiology in the newborn.

Neonatologist-performed echocardiography (NPE) is an indispensable tool in the haemodynamic management of critically ill newborn infants. NPE is used to facilitate timely diagnosis of a patent ductus arteriosus (PDA) in preterm infants and to assess its haemodynamic significance. Before treatment is considered, it is obligatory to confirm structural cardiac normality. Importantly, NPE offers the ability to guide therapeutic interventions, allowing an individualised haemodynamic management approach to the PDA. After discussing PDA pathophysiology, an overview is provided on the role of NPE in the assessment and management of PDA in preterm infants.

Does growth restriction increase the vulnerability to acute ventilation-induced brain injury in newborn lambs? Implications for future health and disease.

Fetal growth restriction (FGR) and preterm birth are frequent co-morbidities, both are independent risks for brain injury. However, few studies have examined the mechanisms by which preterm FGR increases the risk of adverse neurological outcomes. We aimed to determine the effects of prematurity and mechanical ventilation (VENT) on the brain of FGR and appropriately grown (AG, control) lambs. We hypothesized that FGR preterm lambs are more vulnerable to ventilation-induced acute brain injury. FGR was surgically induced in fetal sheep (0.7 gestation) by ligation of a single umbilical artery. After 4 weeks, preterm lambs were euthanized at delivery or delivered and ventilated for 2 h before euthanasia. Brains and cerebrospinal fluid (CSF) were collected for analysis of molecular and structural indices of early brain injury. FGRVENT lambs had increased oxidative cell damage and brain injury marker S100B levels compared with all other groups. Mechanical ventilation increased inflammatory marker IL-8 within the brain of FGRVENT and AGVENT lambs. Abnormalities in the neurovascular unit and increased blood-brain barrier permeability were observed in FGRVENT lambs, as well as an altered density of vascular tight junctions markers. FGR and AG preterm lambs have different responses to acute injurious mechanical ventilation, changes which appear to have been developmentally programmed in utero.

Randomized controlled trial of magnesium sulfate in women at risk of preterm delivery-neonatal cardiovascular effects.

OBJECTIVE: Use of antenatal magnesium sulfate (MgSO(4)) may reduce cerebral palsy in infants born very preterm. Low systemic blood flow in the first day in very preterm infants has been associated with cerebral injury and adverse motor outcome. The aim was to determine the effect of MgSO(4) on systemic blood flow in preterm infants. STUDY DESIGN: Randomized trial of MgSO(4) versus saline placebo given to mothers at risk of delivery before 30 weeks gestation. Echocardiographic monitoring performed at 3 to 5, 10 to 12 and 24 h. RESULT: A total of 48 infants were exposed to MgSO(4) and 39 to placebo. Infants exposed to MgSO(4) were significantly more likely to receive volume expansion (42% versus 21%). Inotrope use did not differ significantly (40% versus 26%). There was no significant difference in mean lowest superior vena cava (SVC) flow or right ventricular output (RVO), or incidence of low SVC flow or RVO in the first 24 h. Infants exposed to MgSO(4) had a significantly higher heart rate and were more likely to have low SVC flow at 10 to 12 h but not other times. CONCLUSION: Antenatal MgSO(4) produced no consistent cardiovascular effects in the infant in the first 24 h. There is no evidence from this study to suggest the mechanism by which antenatal MgSO(4) prevents cerebral palsy is through a cardiovascular effect in the newborn.

The cerebral critical oxygen threshold of ventilated preterm lambs and the influence of antenatal inflammation.

Perinatal inflammation is associated with adverse neurodevelopmental outcomes, which may be partly due to changes in the cerebral oxygen delivery/consumption relationship. We aimed to determine the critical oxygen delivery threshold of the brain of preterm, ventilated lambs and to determine whether the critical threshold is affected by exposure to inflammation in utero. Pregnant ewes received intra-amniotic injection of lipopolysaccharide or saline at 125 or 127 days of gestation. Pulmonary and systemic flow probes and catheters were surgically positioned in the fetus immediately before delivery at 129 days of gestation. After delivery, lambs were ventilated for 90 min using a positive end-expiratory pressure recruitment strategy. Cardio-respiratory variables and blood gases were measured regularly. Systemic and cerebral oxygen delivery, consumption (Fick), and extraction were calculated, and the relationship between cerebral delivery and consumption analyzed. Linear regression was used to define the transition or "critical" oxygen threshold as the point at which the slope of the oxygen delivery/consumption curve changed to be > 10°. Four subgroups were defined according to the calculated critical threshold. A total of 150 measurements were recorded in 18 lambs. Fetal cerebral oxygen consumption was increased by antenatal lipopolysaccharide (P < 0.05). The postnatal critical oxygen threshold was 3.6 ml·kg⁻¹·min⁻¹, corresponding to cerebral oxygen consumption of 0.73 ml·kg⁻¹·min⁻¹. High oxygen delivery and consumption were associated with increased pulmonary and carotid blood flow and systemic extraction compared with low oxygen delivery and consumption. No postnatal effect of antenatal inflammation was observed. Inflammation in utero increases fetal, but not postnatal, cerebral oxygen consumption. Adverse alterations to pulmonary blood flow can result in reduced cerebral blood flow, oxygen delivery, and consumption. Regardless of exposure to inflammation, there is a consistent postnatal relationship between cerebral oxygen delivery and consumption.

Echocardiography and the neonatologist.

Pediatric echocardiography as performed and interpreted by pediatric cardiologists provides details of cardiac structure and function as well as hemodynamic data. Functional echocardiography, in contrast to echocardiography as performed by the cardiologist, is the bedside use of cardiac ultrasound to follow functional and hemodynamic changes longitudinally. Data reflecting cardiac function and systemic and pulmonary blood flow in critically ill preterm and term neonates can be monitored using this method. Functional echocardiography is being developed and driven by neonatologists as an extension of their clinical skills. A wealth of hemodynamic information can be derived from functional echocardiography used for the sick neonate, which provides clinical information different from the assumed underlying physiology. Lack of access to appropriate training programs and interdisciplinary politics is limiting the use of this potentially valuable clinical information. Without the use of functional echocardiography, clinicians are left to speculate as to the underlying pathophysiology of circulatory compromise, and the assumptions they make often are incorrect. For functional echocardiography to fulfill its clinical potential, it needs to be available at any time and at short notice in the neonatal intensive care unit (NICU). Because most NICUs do not have external diagnostic services to provide longitudinal hemodynamic follow-up assessment at the bedside, neonatologists should be able to develop appropriate echocardiographic skills in close collaboration with their cardiologist colleagues.

Clinical detection of low upper body blood flow in very premature infants using blood pressure, capillary refill time, and central-peripheral temperature difference.

OBJECTIVE: To determine the accuracy of blood pressure (BP), capillary refill time (CRT), and central-peripheral temperature difference (CPTd) for detecting low upper body blood flow in the first day after birth. METHODS: A prospective, two centre cohort study of 128 infants born at < 30 weeks gestation. Invasive BP (n = 108), CRT (n = 128), and CPTd (n = 46) were performed immediately before echocardiographic measurement of superior vena cava (SVC) flow at three, 5-10, and 24 hours after birth. RESULTS: Forty four (34%) infants had low SVC flow (< 41 ml/kg/min) in the first day, 13/122 (11%) at three hours, 39/126 (31%) at 5-10 hours, and 4/119 (3%) at 24 hours. CPTd did not detect infants with low flows. Combining all observations in the first 24 hours, CRT > or = 3 seconds had 55% sensitivity and 81% specificity, mean BP < 30 mm Hg had 59% sensitivity and 77% specificity, and systolic BP < 40 mm Hg had 76% sensitivity and 68% specificity for detecting low SVC flow. Combining a mean BP < 30 mm Hg and/or central CRT > or = 3 seconds increases the sensitivity to 78%. CONCLUSIONS: Low upper body blood flow is common in the first day after birth and strongly associated with peri/intraventricular haemorrhage. BP and CRT are imperfect bedside tests for detecting low blood flow in the first day after birth.

Effect of early targeted indomethacin on the ductus arteriosus and blood flow to the upper body and brain in the preterm infant.

OBJECTIVE: To determine if indomethacin given to preterm infants with a large ductus arteriosus (DA) in the first hours of life results in maintained or improved brain and upper body blood (superior vena cava (SVC)) flow. STUDY DESIGN: A randomised, double blind trial of indomethacin v placebo. Echocardiography was performed on 111 infants born at < 30 weeks gestation at 3 and/or 10 hours after birth. Infants were eligible if the DA diameter was > 1.6 mm. Infants were randomised to receive indomethacin 0.2 mg/kg or placebo. Crossover occurred if the DA was still > 1.6 mm. Echocardiography was performed one hour after each treatment. RESULTS: Seventy (63%) infants had a DA > 1.6 mm, with 35 randomised to receive indomethacin and 35 to receive placebo. At one hour there was no difference in DA constriction (indomethacin -20% v placebo -15%), change in SVC flow (-1% v -9%), for right ventricular output (RVO). Two hours after indomethacin, 62 infants had uncontrolled observations, at which time significant ductal constriction had occurred. At this time, infants of > or = 27 weeks gestation had significantly greater increases in SVC flow and RVO than infants of < 27 weeks gestation. Infants with failed ductal constriction had significantly lower initial SVC flow and developed more late grade 3/4 peri/intraventricular haemorrhage (P/IVH). Initial SVC flow, but not ductal constriction, was a significant predictor of late grade 3/4 P/IVH in adjusted analysis. CONCLUSIONS: Indomethacin had minimal effect on ductal constriction and blood flow at one hour compared with placebo. Failure of ductal constriction is associated with low SVC flow and subsequent late severe P/IVH.

Which to measure, systemic or organ blood flow? Middle cerebral artery and superior vena cava flow in very preterm infants.

AIM: To describe, in very preterm babies, postnatal changes in measures of middle cerebral artery (MCA) Doppler variables. To relate these peripheral measures to echocardiographic measures of systemic blood flow and ductal shunting, and to study their relation to subsequent intraventricular haemorrhage (IVH). METHODS: 126 babies born before 30 weeks were studied with serial echocardiography and cerebral and Doppler ultrasound of the MCA at 5, 12, 24, and 48 hours of age. Echocardiographic measures included superior vena cava (SVC) flow and colour Doppler diameter of the ductal shunt. MCA Doppler measures included mean velocity, pulsatility index (PI), and estimated colour Doppler diameter. RESULTS: MCA mean velocity increased whereas the PI decreased significantly over the first 48 hours. Babies with low SVC flow had significantly lower MCA mean velocity and estimated diameter than babies with normal SVC flow. There was no difference in PI. On multivariant analysis, the significant associations with MCA mean velocity were mean blood pressure (MBP), heart rate, SVC flow, and lower calculated vascular resistance. The significant associations with PI were larger ductal diameter and lower mean MBP. The significant associations with MCA diameter were higher SVC flow and lower calculated vascular resistance. After controlling for gestation, there was a highly significant association between lowest SVC flow and subsequent IVH but no association between IVH and lowest MCA mean velocity, estimated diameter, PI, or MBP. CONCLUSIONS: These data are consistent with the speculation that SVC flow is a reflection of cerebral blood flow. Low SVC flow is more strongly associated with subsequent IVH than cerebral artery Doppler measures or MBP.

Survival after an acute pericardial tamponade as a result of percutaneously inserted central venous catheter in a preterm neonate.

Percutaneously inserted central venous catheters (PICC) are used in premature infants to deliver intravenous fluids, total parenteral nutrition (TPN) and medications. This article reports a case in which the baby developed pericardial tamponade within 3 hours of starting TPN through a PICC. This was successfully treated with percutaneous subxiphoid pericardiocentesis. Pericardial tamponade should be suspected in any infant with a PICC line in place, and who suddenly develops shock like symptoms, non-attributable to usual causes.

Low systemic blood flow and hyperkalemia in preterm infants.

OBJECTIVE: Early low systemic blood flow is common in preterm infants. This study examines the relationship among low flow, renal function, and early changes in blood potassium (K(+)). METHODS: Preterm infants (n = 119) born before 30 weeks' gestational age underwent serial Doppler echocardiographic studies. Superior vena cava flow (SVC flow) was assessed as a measure of upper body systemic blood flow uncorrupted by systemic to pulmonary shunts. Serial whole blood K(+) concentrations on each arterial blood gas sample and urinary output in the first 48 hours were recorded. RESULTS: Most infants had a variable degree of rise in K(+) during the first 24 hours of life. The mean rate of rise was 0.17 mmol/L/h, the mean peak K(+) was 5.54 mmol/L, and the mean time of peak K(+) was 20 hours. The peak K(+) occurred after the lowest measured SVC flow in 84% of infants. A significant positive relationship was found between the lowest measured SVC flow and the mean (r = 0.31, P =.001) and peak (r = 0.31, P =.001) K(+) in the first 24 hours. Low SVC flow at 5 hours best predicted the rate of K(+) rise (r = 0.28, P =.002) and at 12 hours best predicted the peak K(+) concentration (r = 0.47, P <.001). The mean minimum SVC flow in the 17 babies who became hyperkalemic was 29.5 mL/kg/min versus 46.2 mL/kg/min in the 102 infants with normokalemia. Urine output in the first 24 hours was significantly lower in the hyperkalemic infants. A K(+) rate rise exceeding 0.12 mmol/L/h in the first 12 hours predicted low SVC flow with 93% accuracy. CONCLUSIONS: The data are consistent with a role for low systemic blood flow leading to reduced urinary output and subsequent hyperkalemia in preterm infants.

Low systemic blood flow in the preterm infant.

Low systemic blood flow in the first hours after birth of a preterm infant is an often unrecognized complication. Traditional measures of cardiovascular adequacy used in the neonatal intensive care unit such as capillary refill time and blood pressure may not identify this problem. Longitudinal measurement of systemic blood flow demonstrates a falling off of blood flow in the first 6-12 h after birth, often to less than half of normal, before a gradual return to normal values by 24-48 h of age. Identification and appropriate treatment of this reduction in flow may assist in preventing some of the complications of prematurity.

Ductal shunting, high pulmonary blood flow, and pulmonary hemorrhage.

OBJECTIVE: To describe the relationship among ductal shunting, estimated pulmonary blood flow, and pulmonary hemorrhage in very preterm infants. STUDY DESIGN: A total of 126 babies born before 30 weeks' gestation (median gestation 27 weeks, range 23 to 29 weeks) underwent echocardiography at 5, 12, 24, and 48 hours of age; measurements included right and left ventricular output, superior vena cava flow, and color Doppler diameter of any ductal shunt. Pulmonary blood flow was derived from the sum of right ventricular output and estimated ductal shunt flow. RESULTS: Twelve (9.5%) babies had a pulmonary hemorrhage at a mean age of 38 hours. Compared with the rest of the cohort, these 12 babies were less likely to have had antenatal steroids (59% vs 90%) and were less mature (26 weeks vs 27 weeks). At the echocardiogram closest to the pulmonary hemorrhage, 11 (92%) of the 12 babies had a significant patent ductus arteriosus >1.6 mm in diameter (median 2 mm, range 0.7 to 2.4 mm), and the median pulmonary blood flow was 326 mL/kg/min (range 210 to 598 mL/kg/min). These measurements were significantly higher than those found in the rest of the cohort in the same period (median duct diameter 0.5 mm [range 0 to 2.9 mm], median pulmonary blood flow 237 mL/kg/min [range 107 to 569 mL/kg/min]). At 5-hour echocardiography the babies with pulmonary hemorrhage had significantly larger diameter ducts but similar pulmonary blood flow. CONCLUSIONS: Pulmonary hemorrhage in preterm babies is associated with significant ductal shunting and high estimated pulmonary blood flow.

Low superior vena cava flow and intraventricular haemorrhage in preterm infants.

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 28 v 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.

Superior vena cava flow in newborn infants: a novel marker of systemic blood flow.

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.

Prostacyclin concentrations and transitional circulation in preterm infants requiring mechanical ventilation.

AIM: To describe the association between early postnatal prostacyclin concentrations in preterm infants; echocardiographic measurements of ductal diameter and ventricular output and clinical outcomes of intraventricular haemorrhage (IVH) and patent ductus arteriosus (PDA). METHODS: Forty nine preterm infants born before 30 weeks of gestational age (median birthweight 980 g, median gestational age 27 weeks) underwent echocardiographic studies at 5, 12, 24 and 48 hours of postnatal age. Measurements included ventricular outputs and the ductal shunt diameter as a measure of the shunt size. Simultaneous measurements of blood pressures, mean airway pressure and inspired fraction of oxygen (FIO2) were recorded. A blood sample for the prostacyclin metabolite 6-ketoprostaglandin F1-alpha (6KPGF1 alpha) was taken at the 5 and 24 hour echocardiogram. RESULTS: The mean 6KPGF1 alpha concentrations were higher than adult concentrations at 5 (515 pg/ml) and 24 (255 pg/ml) hours. There was no association with gestational age. Raised 6KPGF1 alpha concentrations were related to increased need for mechanical ventilation and severity of respiratory disease. At 5 hours, increased 6KPGF1 alpha concentrations were associated with larger PDA and at 24 hours with larger PDA and higher left ventricular output. Infants with higher 6KPGF1 alpha concentrations were more likely to develop clinically significant PDA. There was no association between early measurements of 6KPGF1 alpha and IVH. CONCLUSIONS: Early postnatal prostacyclin concentrations are markedly raised in preterm infants, particularly in those with more severe lung disease. Raised 6KPGF1 alpha concentrations were associated with an increased ductal diameter and subsequent PDA, but not IVH.

Range of echocardiographic findings in term neonates with high oxygen requirements.

AIMS: To examine the hypothesis that right to left shunting occurs mainly in the lungs rather than through the fetal channels in neonates. METHODS: Thirty two term babies requiring over 70% oxygen had daily colour Doppler echocardiograms until recovery. Measurements included left ventricular fractional shortening, right and left ventricular outputs, colour and pulsed Doppler ductal and atrial shunting and systolic pulmonary artery pressure (SPAP) derived from ductal shunt or tricuspid incompetence velocities. RESULTS: The babies were retrospectively classified into a respiratory group (n = 19) and a persistent pulmonary hypertension (PPHN) group (n = 13) on the basis of clinical history and radiology. At the initial echocardiogram, just 50% of babies had suprasystemic SPAP. Despite better oxygenation, more of the PPHN group had suprasystemic PAP (85% vs 26%). A correlation between SPAP and Oxygen index (OI) was present only in the respiratory group (r = 0.7). Low ventricular outputs (< 150 ml/kg/min) were common in both groups (53% and 79%). The respiratory group had more closed ducts (47% vs 0%) and those ducts which were patient were more constricted (1.75 mm vs 2.6 mm). Pure right to left ductal shunts were seen in just 15% and pure right to left atrial shunts in just 6% of all babies. The serial echocardiograms showed that SPAP fell and ducts closed well before oxygenation improved. Ventricular outputs increased with age in both groups. CONCLUSIONS: Apart from early on in the sickest babies with a primarily respiratory diagnosis and the babies with primary PPHN, most right to left shunting occurred at an intrapulmonary level.