Mary Paradisis

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.

Decreased aEEG Continuity and Baseline Variability in the First 48 Hours of Life Associated With Poor Short-Term Outcome in Neonates Born Before 29 Weeks Gestation

Amplitude-integrated electroencephalography (aEEG) provides us with a method of assessing brain activity in critically ill neonates. In extremely premature neonates, the aEEG trace is predominantly discontinuous, making it difficult to distinguish between a “normal” and “abnormal” trace. We measured aEEG activity in the first 48 h of life in neonates born before 29-wk gestation and used both visual and quantitative analysis of the aEEG data to assess differences in neonates with poor short-term outcome [death or peri/intraventricular hemorrhage (P/IVH)] compared with those who survived without P/IVH to identify features of an abnormal aEEG. On quantitative analysis, EEG continuity <80% at 10-μV level was a sensitive and specific marker of poor short-term outcome. By using this marker, we identified 83% of neonates who died or developed grade 3 or 4 IVH and 60% of neonates who developed grades 1 or 2 IVH, with a positive predictive value for death or any IVH of 73% and a negative predictive value of 86%. Absence of sleep-wake cycling with baseline variability <2 μV was the strongest predictor of outcome using visual analysis alone.

Population pharmacokinetics and dosing regimen design of milrinone in preterm infants

Aims: To define the pharmacokinetics of milrinone in very preterm infants and determine an optimal dose regimen to prevent low systemic blood flow in the first 12 h after birth. Methods: A prospective open-labelled, dose-escalation pharmacokinetic study was undertaken in two stages. In stage one, infants received milrinone at 0.25 μg/kg/min (n = 8) and 0.5 μg/kg/min (n = 11) infused from 3 to 24 h of age. Infants contributed 4–5 blood samples for concentration–time data which were analysed using a population modelling approach. A simulation study was used to explore the optimal dosing regimen to achieve target milrinone concentrations (180–300 ng/ml). This milrinone regimen was evaluated in stage two (n = 10). Results: Infants (n = 29) born before 29 weeks gestation were enrolled. Milrinone pharmacokinetics were described using a one-compartment model with first-order elimination rate, with a population mean clearance (CV%) of 35 ml/h (24%) and volume of distribution of 512 ml (21%) and estimated half-life of 10 h. The 0.25 and 0.5 μg/kg/min dosage regimens did not achieve optimal milrinone concentration-time profiles to prevent early low systemic blood flow. Simulation studies predicted a loading infusion (0.75 μg/kg/min for 3 h) followed by maintenance infusion (0.2 μg/kg/min until 18 h of age) would provide an optimal milrinone concentration profile. This was confirmed in stage two of the study. Conclusion: Population pharmacokinetic modelling in the preterm infant has established an optimal dose regimen for milrinone that increases the likelihood of achieving therapeutic aims and highlights the importance of pharmacokinetic studies in neonatal clinical pharmacology.

Neurodevelopmental Outcomes of Premature Infants Treated for Patent Ductus Arteriosus: A Population-Based Cohort Study.

OBJECTIVE To compare neurodevelopmental outcomes of extremely preterm infants diagnosed with patent ductus arteriosus (PDA) who were treated medically or surgically and those who were not diagnosed with PDA or who did not undergo treatment for PDA. STUDY DESIGN This retrospective population-based cohort study used data from a geographically defined area in New South Wales and the Australian Capital Territory served by a network of 10 neonatal intensive care units. Patients included all preterm infants born at <29 completed weeks of gestation between 1998 and 2004. Moderate/severe functional disability at 2-3 years corrected age was defined as developmental delay, cerebral palsy requiring aids, sensorineural or conductive deafness (requiring bilateral hearing aids or cochlear implant), or bilateral blindness (best visual acuity of <6/60). RESULTS Follow-up information at age 2-3 years was available for 1473 infants (74.8%). Compared with infants not diagnosed with a PDA or who did not receive PDA treatment for PDA, those with medically treated PDA (aOR, 1.622; 95% CI, 1.199-2.196) and those with surgically treated PDA (aOR, 2.001; 95% CI, 1.126-3.556) were at significantly greater risk for adverse neurodevelopmental outcomes at age 2-3 years. CONCLUSION Our results demonstrate that treatment for PDA may be associated with a greater risk of adverse neurodevelopmental outcome at age 2-3 years. This was particularly so among infants born at <25 weeks gestation. These results may support permissive tolerance of PDAs; however, reasons for this association remain to be elucidated through carefully designed prospective trials.

Relationship between systemic blood flow, blood pressure, inotropes, and aEEG in the first 48[thinsp]h of life in extremely preterm infants

Background:Significant hemodynamic changes occur immediately after birth in preterm infants. Amplitude-integrated electroencephalography (aEEG) provides a method of assessing brain activity in sick neonates; however, the relationship among systemic blood flow, blood pressure (BP), and aEEG is not clear.Methods:Quantitative measures of aEEG continuity and amplitude were correlated with superior vena cava (SVC) flow, right-ventricular output (RVO), and BP at 12, 24, and 48 h in 92 infants born at <29 wk gestation.Results:SVC flow, RVO, BP, aEEG amplitude, and EEG continuity all increased from 12 to 48 h. SVC flow at 12 h, but not 24 or 48 h, was significantly associated with aEEG amplitude after adjustment for gestational age (GA) and severity of illness markers (r2 = 0.21, P = 0.004). RVO and BP showed less consistent associations with aEEG parameters. Infants receiving inotropes at 12 h, including those in whom cardiovascular parameters had normalized, had significantly lower aEEG amplitude (P < 0.01) and EEG continuity at the 10, 25, and 50 μV levels (P < 0.01) at 12, 24, and 48 h than neonates who were not receiving inotropes.Conclusion:aEEG measurements in the first 48 h of life are related to SVC flow and treatment with inotropes at 12 h of life in extremely preterm infants.

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

Objective:Use of antenatal magnesium sulfate (MgSO4) 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 MgSO4 on systemic blood flow in preterm infants.Study Design:Randomized trial of MgSO4 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 MgSO4 and 39 to placebo. Infants exposed to MgSO4 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 MgSO4 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 MgSO4 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 MgSO4 prevents cerebral palsy is through a cardiovascular effect in the newborn.

Dwell time and risk of central-line-associated bloodstream infection in neonates

BACKGROUND Umbilical venous catheters (UVCs) or peripherally inserted central catheters (PICCs), widely used in high-risk neonates, may have a threshold dwell time for subsequent increased risk of central-line-associated bloodstream infection (CLABSI). AIM To evaluate the CLABSI risks in neonates having either UVC, PICC, or those having both sequentially. METHODS The study included 3985 infants who had UVC or PICC inserted between 2007 and 2009 cared for in 10 regional neonatal intensive care units: 1392 having UVC only (group 1), 1317 PICC only (group 2), and 1276 both UVC and PICC (group 3). FINDINGS There were 403 CLABSIs among 6000 venous catheters inserted, totalling 43,302 catheter-days. CLABSI rates were higher in group 3 infants who were of lowest gestation (16.9 per 1000 UVC-days and 12.5 per 1000 PICC-days; median: 28 weeks) when compared with group 1 (3.3 per 1000 UVC-days; 37 weeks) and group 2 (4.8 per 1000 PICC-days; 30 weeks). Life table and Kaplan-Meier hazard analysis showed that UVC CLABSI rate increased stepwise to 42 per 1000 UVC-days by day 10, with the highest rate in group 3 (85 per 1000 UVC-days). PICC CLABSI rates remained relatively stable at 12-20 per 1000 PICC-days. Compared to PICC, UVC had a higher adjusted CLABSI risk controlled for dwell time. Among group 3, replacing UVC electively before day 4 may have a trend of lower CLABSI risk than late replacement. CONCLUSION There was no cut-off duration beyond which PICC should be removed electively. Early UVC removal and replacement by PICC before day 4 might be considered.

133 Pilot Study of Milrinone for Prevention of Low Systemic Blood Flow in Very Preterm Infants

Background: Low systemic blood flow as measured by superior vena cava (SVC) flow is common in very preterm infants. It is strongly associated with IVH and disability and may be caused by poor cardiac adaptation to high vascular resistance (VR)[1]. Because of limited efficacy of therapeutic circulatory support using traditional inotropes[2], we are exploring a preventative approach using Milrinone, an inodilator that increases contractility and reduces VR. The aim of this study was to examine the safety and pharmaco-kinetics (PK) of Milrinone infusion given prophylactically from 3 hours to very preterm infants (median GA 26w) at risk of low blood flow.Methods: A dose escalation and PK study was undertaken, starting with low dose infusion (0.25mcg/kg/min) followed by a higher dose (0.5mcg/kg/min) from 3 until 24 hours of age. Monitoring was with serial echocardiography and head ultrasound (HUS). Serial blood Milrinone levels were taken for PK analysis. Using this data, a population modelling and simulation approach established an optimal dosing profile that fulfilled our preventative aim and achieved target drug levels. This regimen was to load with 0.75mcg/kg/min for 3 hours and maintain with 0.2mcg/kg/min until 18 hours of age. The primary outcome was maintenance of SVC flow >45ml/kg/min in the absence of severe hypotension. Secondary outcomes included intraventricular haemorrhage (IVH). Exit criteria: BP >24mmHg for over 30 mins unresponsive to inotropes.Results: At both infusion rates in the dose escalation phase of study, target blood levels were not achieved quickly enough, only 64% of babies maintained SVC flow and Milrinone levels were high by 24 hrs. Ten infants were then studied using the optimised regimen. All maintained SVC flow >45 ml/kg/min (compared to 40% in an historical cohort) and had drug concentrations within the target therapeutic range. No infant met exit criteria. No immediate adverse effects attributable to Milrinone were noted. There were 3 late deaths attributable to severe respiratory failure and NEC and one from late diagnosis of lethal congenital malformation.Conclusion: Population PK modelling in the preterm infant has been able to establish an optimal dose regimen for Milrinone that fulfils preventative aims. These encouraging results are currently being investigated for therapeutic efficacy within a pilot RCT.