Martin Kluckow

Early echocardiographic prediction of symptomatic patent ductus arteriosus in preterm infants undergoing mechanical ventilation

OBJECTIVE To identify early echocardiographic markers allowing prediction of subsequent symptomatic patent ductus arteriosus (PDA). METHODS One hundred sixteen preterm infants ( < 1500 gm) requiring mechanical ventilation underwent echocardiography at a mean postnatal age of 19 hours (range, 7 to 31 hours). Four potential markers were studied: the left atrial to aortic root ratio, pulsed Doppler signal within the course of the duct (ductal diameter), and the direction of postductal aortic diastolic flow. Subsequent ductal closure or significant patency (if suspected clinically) was confirmed echocardiographically. RESULTS A significant PDA developed in 42 infants (36%). Ductal diameter was the most accurate echocardiographic marker in predicting subsequent significant most accurate echocardiographic marker in predicting subsequent significant PDA. With a ductal diameter of 1.5 mm or greater there were 34 true-positive, 11 false-positive, 63 true-negative, and 8 false-negative results, giving a positive likelihood ratio of 5.5 and a negative likelihood ratio of 0.22 for prediction of development of a PDA requiring treatment. The sensitivity was 81% and the specificity was 85%. Only one infant older than 28 weeks of gestational age had a significant PDA, and limiting the analysis to infants younger than 29 weeks of gestation further improved the predictive accuracy of ductal diameter. The positive likelihood ratio was 8.1 and the negative likelihood ratio was 0.19, with a sensitivity of 83% and a specificity of 90%. CONCLUSION Color Doppler measurement of the internal ductal diameter allows early prediction of significant PDA in preterm infants.

Relationship between blood pressure and cardiac output in preterm infants requiring mechanical ventilation

OBJECTIVE To assess the contribution of cardiac output in determining the blood pressure of preterm infants and to identify other factors that may be important. METHODS Sixty-seven preterm infants requiring mechanical ventilation (median birth weight, 1015 gm: median gestational age, 28 weeks) underwent on echocardiographic study at on average age of 19 hours (range, 7 to 31 hours). Measurements taken included left ventricular ejection fraction, left and right ventricular outputs by means of pulsed Doppler and the diameter of both the ductal and atrial shunt jets with the use of color Doppler as a measure of the size of shunt. Simultaneous measurements of intraarterial blood pressures, mean airway pressure, and inspired fraction of oxygen were recorded. RESULTS After we allowed for the influence of ductal shunting, the correlation between the left ventricular output and mean arterial blood pressure was significant but weak (r = 0.38). There were infants with low blood pressures and normal cardiac outputs, and conversely there were infants with low cardiac outputs and normal blood pressure. The infants with a mean arterial blood pressure of less than 30 mm Hg had a significantly lower gestational age (27 vs 28 weeks), higher mean airway pressure (9.0 vs 7.0 cm H2O), larger ductal diameter (1.6 mm vs 0.7 mm) and a lower systemic vascular resistance (163 vs 184 mm Hg/L per minute per kilogram of body weight). Multilinear regression identified higher mean airway pressure and larger ductal diameter as significant negative influences on mean arterial blood pressure, with higher gestational age and higher left ventricular output as significant positive influences. CONCLUSIONS Normal blood pressure cannot necessarily be equated with normal systemic now. These data emphasize the importance of other influences, and in particular that of varying systemic vascular resistance, in the determination of blood pressure in preterm infants.

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.

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 ⩾ 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 ⩾ 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.

Low superior vena cava flow and effect of inotropes on neurodevelopment to 3 years in preterm infants

OBJECTIVE. The goal was to report the 1- and 3-year outcomes of preterm infants with low systemic blood flow in the first day and the effect of dobutamine versus dopamine for treatment of low systemic blood flow. METHODS. A cohort of 128 infants born at <30 weeks of gestation underwent echocardiographic measurement of superior vena cava flow at 3, 10, and 24 hours of age. Forty-two infants with low superior vena cava flow (<41 mL/kg per minute) were assigned randomly to dobutamine or dopamine. Surviving infants underwent blinded neurodevelopmental assessments at corrected ages of 1 and 3 years. RESULTS. Seventy-six of 87 surviving infants were seen at 1 year and 67 at 3 years. Forty-four infants had low superior vena cava flow. At 3 years, with adjustment for perinatal risk factors, death was predicted by low superior vena cava flow, lower gestational age, and low 5-minute Apgar score. Substantial reductions in the Griffiths General Quotient were associated with low superior vena cava flow and birth weight of <10th percentile. Infants with low flow had significant reductions in personal-social, hearing and speech, and performance subscales. Death or disability at 3 years was predicted by low superior vena cava flow and lower gestational age. For infants treated with inotropes, no significant differences were found in clinical outcomes, except for reduced rates of late severe periventricular/intraventricular hemorrhage in the dobutamine group. At 3 years, infants in the dopamine group had significantly more disability and a lower Griffiths General Quotient. At the latest time measured, however, combined rates of death or disability were similar. CONCLUSIONS. Early low superior vena cava flow was associated with substantial rates of death, morbidity, and developmental impairments. No difference was found in combined rates of death and disability for infants assigned randomly to dopamine or dobutamine.

Randomized Trial of Milrinone Versus Placebo for Prevention of Low Systemic Blood Flow in Very Preterm Infants

OBJECTIVE To assess the effectiveness of early prophylactic milrinone versus placebo for prevention of low systemic blood flow in high-risk preterm infants. STUDY DESIGN Double-blind randomized placebo controlled trial of milrinone (loading dose 0.75 microg/kg/min for 3 hours then maintenance 0.2 microg/kg/min until 18 hours after birth) versus placebo. Infants born <30 weeks gestational age and <6 hours of age were eligible and were monitored with serial echocardiography, head ultrasound scanning, and continuous invasive blood pressure. Primary outcome was maintenance of superior vena cava (SVC) flow > or =45 mL/kg/min through the first 24 hours. The exit criterion was hypotension unresponsive to volume and inotropes. RESULTS Ninety infants were enrolled, equal proportions maintained SVC flow > or =45 mL/kg/min after treatment commenced. No significant difference was observed in SVC flow, right ventricular output, and blood pressure during the first 24 hours; or grades 3 to 4 periventricular/intraventricular hemorrhage and death. Heart rate was higher and constriction of the ductus was slower in the infants randomized to milrinone. CONCLUSIONS Milrinone did not prevent low systemic blood flow during the first 24 hours in very preterm infants, and no adverse effects were attributable to milrinone. Use of a preventative treatment with rescue model allowed comparison of an inotrope with placebo in this high-risk group of infants.

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.

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.

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).

Point-of-care ultrasound in the neonatal intensive care unit: international perspectives

To explore international variation in implementation of point-of-care ultrasound in the neonatal intensive care unit (NICU), contributions were invited from neonatologists and paediatric cardiologists in six countries. The contributors show variation in national implementation that ranges from almost total coverage through to a minority of NICUs having point-of-care ultrasound capability. To a varying degree in all systems the main barriers have been concerns from the consultative specialties that traditionally use ultrasound, relating to the risk of misdiagnosis but also involving different clinical needs, liability concerns and lack of outcome-based evidence. All contributors agreed that safe point-of-care ultrasound depends on close collaboration with the consultative specialties and also that there is a need to develop training and accreditation structures for neonatologists using ultrasound.