David A Osborn

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.

Clinical Use of Probiotics in Pediatric Allergy (cuppa): A World Allergy Organization Position Paper

BackgroundProbiotic administration has been proposed for the prevention and treatment of specific allergic manifestations such as eczema, rhinitis, gastrointestinal allergy, food allergy, and asthma. However, published statements and scientific opinions disagree about the clinical usefulness.ObjectiveA World Allergy Organization Special Committee on Food Allergy and Nutrition review of the evidence regarding the use of probiotics for the prevention and treatment of allergy.MethodsA qualitative and narrative review of the literature on probiotic treatment of allergic disease was carried out to address the diversity and variable quality of relevant studies. This variability precluded systematization, and an expert panel group discussion method was used to evaluate the literature. In the absence of systematic reviews of treatment, meta-analyses of prevention studies were used to provide data in support of probiotic applications.ResultsDespite the plethora of literature, probiotic research is still in its infancy. There is a need for basic microbiology research on the resident human microbiota. Mechanistic studies from biology, immunology, and genetics are needed before we can claim to harness the potential of immune modulatory effects of microbiota. Meanwhile, clinicians must take a step back and try to link disease state with alterations of the microbiota through well-controlled long-term studies to identify clinical indications.ConclusionsProbiotics do not have an established role in the prevention or treatment of allergy. No single probiotic supplement or class of supplements has been demonstrated to efficiently influence the course of any allergic manifestation or long-term disease or to be sufficient to do so. Further epidemiologic, immunologic, microbiologic, genetic, and clinical studies are necessary to determine whether probiotic supplements will be useful in preventing allergy. Until then, supplementation with probiotics remains empirical in allergy medicine. In the future, basic research should focus on homoeostatic studies, and clinical research should focus on preventive medicine applications, not only in allergy. Collaborations between allergo-immunologists and microbiologists in basic research and a multidisciplinary approach in clinical research are likely to be the most fruitful.

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.

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.

Left ventricular contractility in extremely premature infants in the first day and response to inotropes

The aim was to assess myocardial contractility in infants born <30 wk gestation developing low systemic blood flow (SBF) in the first day, and the effect of dobutamine versus dopamine. Superior vena cava (SVC) flow was used as a measure of SBF at 3, 10, and 24 h (n = 106). Infants with low SVC flow randomized to dopamine or dobutamine. Myocardial contractility was determined by the relationship between left ventricular (LV) mean velocity of circumferential fiber shortening (mVcfs) and wall stress. Infants who developed low SVC flow had significantly worse myocardial contractility at 3 h, but not 10 h. At 24 h, low-flow infants had lower than expected mVcfs for any given LV stress. In 37 infants randomized to inotrope, there was no significant difference in contractility at 10 μg/kg/min. At 20 μg/kg/min (n = 21), dopamine increased whereas dobutamine decreased LV stress. Infants on dobutamine had significantly lower than expected mVcfs for any given LV stress compared with infants on dopamine. Contractility was not improved by either inotrope at either dose. In conclusion, infants developing low SVC flow in the first day have worse myocardial contractility at 3 h. Neither inotrope increased contractility, but dopamine increased LV stress at 20 μg/kg/min.

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 ⩾ 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.

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.

Cardiorespiratory effects of changes in end expiratory pressure in ventilated newborns

Background: Positive pressure ventilation in premature infants can improve oxygenation but may diminish cerebral blood flow and cardiac output. Low superior vena cava (SVC) flow increases risk of intraventricular haemorrhage, and higher mean airway pressure is associated with low SVC flow. Whether this is a direct effect of positive pressure ventilation or a reflection of severity of lung disease is not known. This study aimed to determine if positive end expiratory pressure (PEEP) in ventilated newborns could be increased without clinically relevant cardiorespiratory changes. Method: Ventilated newborns were studied before and 10 min after increasing PEEP (5 cm H2O to 8 cmH2O) and again when PEEP returned to baseline. Echocardiographic and respiratory function measurements were collected during the intervention. Results: In 50 infants, increased PEEP was associated with a non-significant difference in mean SVC flow of −5 ml/kg/min (95% CI −12 to 3 ml/kg/min) but a significant reduction in right ventricular output of 17 ml/kg/min (95% CI 5 to 28 ml/kg/min). The increase in lung compliance was non-significant (median difference 0.02 ml/cmH2O/kg) and the decrease in lung resistance (18 cmH2O/l/s; 95% CI 10 to 26 cm H2O/l/s) was significant. Changes (%) in lung compliance and SVC flow, when corrected for Paco2, were positively associated (regression coefficient 0.4%; 95% CI 0.2% to 0.6%). Conclusion: A short-term increase in PEEP does not lead to significant changes in systemic blood flow, although 36% of infants in the present study had clinically important changes in flow (±25%). The intervention can improve dynamic lung function, especially airway resistance. Improvements in compliance tend to be associated with improvements in blood flow.

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.)