Klaus Børch

Blood Flow Distribution in the Normal Human Preterm Brain

Disturbances in cerebral blood flow (CBF) are a major factor in the etiology and pathogenesis of cerebral damage in the neonate. As most animals are more mature at birth than man, extrapolation from animal studies to the human is questionable. Therefore, we have measured regional CBF (rCBF) in preterm infants. rCBF flow was measured in 12 normotensive and normoxic preterm infants [mean birth weight 915 g (range 550 to 2680 g), mean gestational age 27.7 wk (25 to 32 wk)]. All infants had a normal cerebral ultrasound examination. rCBF was measured using a mobile brain dedicated fast-rotating four-head multidetector system specially designed for neonatal studies. The tracer was 99mTc-labeled D,L-hexamethylpropylenamine oxime in a dose of 4 Mbq/kg. rCBF of the subcortical white matter was 0.53(0.48-0.58) of the global CBF. After correction for scattered radiation, the estimate of rCBF to the white matter was reduced to 0.39 (0.36-0.42). The flow to the basal ganglia was 2.33 (2.08-2.59) times the global CBF. After correction for partial volume effect, the cortical flow was higher than the flow to the basal ganglia and highest in the frontotemporal cortex (motor cortex). The flow to the cerebellum was of the same magnitude as the flow to the basal ganglia, but with a significantly higher variation. rCBF in 12 preterm infants showed a flow distribution similar to flow in other newborn mammals. The gray-white matter contrast, however, was greater. This new information, combined with existing data showing low global CBF, suggests that blood flow to the white matter in the preterm human neonate is extremely low.

Characteristics of Neonatal Units That Care for Very Preterm Infants in Europe: Results From the MOSAIC Study

OBJECTIVES. We sought to compare guidelines for level III units in 10 European regions and analyze the characteristics of neonatal units that care for very preterm infants. METHODS. The MOSAIC (Models of Organising Access to Intensive Care for Very Preterm Births) project combined a prospective cohort study on all births between 22 and 31 completed weeks of gestation in 10 European regions and a survey of neonatal unit characteristics. Units that admitted ≥5 infants at <32 weeks of gestation were included in the analysis (N = 111). Place of hospitalization of infants who were admitted to neonatal care was analyzed by using the cohort data (N = 4947). National or regional guidelines for level III units were reviewed. RESULTS. Six of 9 guidelines for level III units included minimum size criteria, based on number of intensive care beds (6 guidelines), neonatal admissions (2), ventilated patients (1), obstetric intensive care beds (1), and deliveries (2). The characteristics of level III units varied, and many were small or unspecialized by recommended criteria: 36% had fewer than 50 very preterm annual admissions, 22% ventilated fewer than 50 infants annually, and 28% had fewer than 6 intensive care beds. Level II units were less specialized, but some provided mechanical ventilation (57%) or high-frequency ventilation (20%) or had neonatal surgery facilities (17%). Sixty-nine percent of level III and 36% of level I or II units had continuous medical coverage by a qualified pediatrician. Twenty-two percent of infants who were <28 weeks of gestation were treated in units that admitted fewer than 50 very preterm infants annually (range: 2%–54% across the study regions). CONCLUSIONS. No consensus exists in Europe about size or other criteria for NICUs. A better understanding of the characteristics associated with high-quality neonatal care is needed, given the high proportion of very preterm infants who are cared for in units that are considered small or less specialized by many recommendations.

White Matter Injury in the Preterm Neonate: The Role of Perfusion

The preterm infant is at special risk of white matter injury. It was hypothesized long ago that ischemia is the principal etiology. The commonly used experimental animals for perinatal brain injury research may differ importantly from humans as regards the white matter. Therefore, evidence from human neonates that the white matter is selectively exposed to ischemia is relevant. Blood flow to the white matter appears to be particularly low in the premature human infant, with only 17% of flow to the gray matter. Furthermore, the blood flow to the white matter appears to be selectively reduced when blood pressure is low. There are important methodological limitations to all the studies reviewed; whereas the hypothesis has not had strong support, it has not been refuted. It appears wise to consider ischemia to the white matter a real threat in sick preterm infants.

Cerebral white matter blood flow and arterial blood pressure in preterm infants

It is generally assumed that one reason why white matter injury is common in preterm infants is the relatively poor vascular supply.

99mTc-HMPAO as a tracer of cerebral blood flow in newborn infants

Studies on the kinetics of 99mTc-D,L-hexamethylpropylene amine oxime (99mTc-HMPAO) in adults have shown that it is not an ideal tracer of CBF because it underestimates high-flow areas. Knowledge of the kinetics of the tracer is important in evaluating the studies. The kinetics of 99mTc-HMPAO in infants may be different from that in adults, therefore, we examined the cerebral uptake and retention of 99mTc-HMPAO in neonates and estimated the degree of brain-to-blood back diffusion by comparing corresponding 133Xe flow images and 99mTc-HMPAO distribution images. In addition, we measured the urinary excretion of 99mTc-HMPAO. Regional CBF was measured using a mobile brain dedicated, fast-rotating, four-head multidetector system specially designed for neonatal studies. Tracers were 99mTc-HMPAO (4 MBq/kg) and 133Xe (500 MBq/kg). Cerebral uptake and leak-out of 99mTc-HMPAO were measured by a single scintillation crystal placed over the frontoparietal part of the infants head. The cerebral retention of 99mTc-HMPAO was analyzed in 50 infants. The mean gestational age and birth weight (95% confidence interval) were 34.4 weeks (32.2–35.7) and 2,326 g (1,954–2,995), respectively. The cerebral uptake of 99mTc-HMPAO was examined in 16 of the 50 infants, and activity during 24 h was monitored in five. In 11 infants, corresponding 133Xe studies were performed. Urinary excretion was studied in 12 infants. The maximal activity in the brain was reached 90s after i.v. injection and was 104% (98–111) of the stable level, which was reached approximately 3 min after the injection. The decay corrected leakout of the tracer during the following 24 h was 1.0% (0.4–1.5) per hour. The cerebral retention was calculated at 6.8% (6.1–7.6), highest in the group of ictal studies and lowest in premature infants with intracranial hemorrhage. The mean value of the fixation/clearance ratio α was estimated at 3.4 (2.8–4.4). The mean urinary excretion over 24 h was 19.5% (11.4–27.7) and was significantly related to renal function as indicated by serum urea (p = 0.02 r2 = 0.55). A four-compartment model describing the kinetics of 99mTc-HMPAO is shown to be valid in neonates. The cerebral retention of the tracer is higher in neonates because of higher extraction and lower initial back diffusion from brain to blood. In linearizing 99mTc-HMPAO distribution images, a smaller correction is necessary, and we propose a value of the correction factor of 3.4. In this way, 99mTc-HMPAO is a more reliable tracer of the distribution of CBF in neonates compared with adults. The urinary excretion is significantly reduced compared with adults, and the radiation dose to the bladder wall is reduced. The effective dose is 0.3 mSv/MBq/kg.

Association of Short Antenatal Corticosteroid Administration-to-Birth Intervals With Survival and Morbidity Among Very Preterm Infants: Results From the EPICE Cohort

Importance Administration-to-birth intervals of antenatal corticosteroids (ANS) vary. The significance of this variation is unclear. Specifically, to our knowledge, the shortest effective administration-to-birth interval is unknown. Objective To explore the associations between ANS administration-to-birth interval and survival and morbidity among very preterm infants. Design, Setting, and Participants The Effective Perinatal Intensive Care in Europe (EPICE) study, a population-based prospective cohort study, gathered data from 19 regions in 11 European countries in 2011 and 2012 on 4594 singleton infants with gestational ages between 24 and 31 weeks, without severe anomalies and unexposed to repeated courses of ANS. Data were analyzed November 2016. Exposure Time from first injection of ANS to delivery in hours and days. Main Outcomes and Measures Three outcomes were studied: in-hospital mortality; a composite of mortality or severe neonatal morbidity, defined as an intraventricular hemorrhage grade of 3 or greater, cystic periventricular leukomalacia, surgical necrotizing enterocolitis, or stage 3 or greater retinopathy of prematurity; and severe neonatal brain injury, defined as an intraventricular hemorrhage grade of 3 or greater or cystic periventricular leukomalacia. Results Of the 4594 infants included in the cohort, 2496 infants (54.3%) were boys, and the mean (SD) gestational age was 28.5 (2.2) weeks and mean (SD) birth weight was 1213 (400) g. Mortality for the 662 infants (14.4%) unexposed to ANS was 20.6% (136 of 661). Administration of ANS was associated with an immediate and rapid decline in mortality, reaching a plateau with more than 50% risk reduction after an administration-to-birth interval of 18 to 36 hours. A similar pattern for timing was seen for the composite mortality or morbidity outcome, whereas a significant risk reduction of severe neonatal brain injury was associated with longer administration-to-birth intervals (greater than 48 hours). For all outcomes, the risk reduction associated with ANS was transient, with increasing mortality and risk for severe neonatal brain injury associated with administration-to-birth intervals exceeding 1 week. Under the assumption of a causal relationship between timing of ANS and mortality, a simulation of ANS administered 3 hours before delivery to infants who did not receive ANS showed that their estimated decline in mortality would be 26%. Conclusions and Relevance Antenatal corticosteroids may be effective even if given only hours before delivery. Therefore, the infants of pregnant women at risk of imminent preterm delivery may benefit from its use.

Regional Cerebral Blood Flow During Hypotension and Hypoxemia in Preterm Infants 28

Introduction: Periventricular leucomalacia (PVL) is hypothesized to be due to an impaired autoregulation leading to ischemia of the periventricular white matter. The aim of this study was to examine if hypotension or hypoxemia leads to a relatively decreased blood flow to the cerebral white matter in preterm infants.

Regional cerebral blood volume (CBV) is overestimated by Near-infrared spectrophotometry (NIRS) validation against Single Photon Emission Computerized Tomography (SPECT) in newborn piglets. 29

Regional cerebral blood volume (CBV) is overestimated by Near-infrared spectrophotometry (NIRS) validation against Single Photon Emission Computerized Tomography (SPECT) in newborn piglets. 29

Blood Flow to Cerebral White Matter in Preterm Infants 32

Introduction: According to the major hypothesis distortions in CBF is one of the substantial factors in the etiology and pathogenesis of cerebral damage in the neonate. To estimate the flow to the subcortical white matter we have examined regional cerebral blood flow in twelve preterm infants.

25 WIDESPREAD REGIONAL CEREBRAL BLOOD FLOW DISTURBANCES IN PRETERM INFANTS WITH INTRACEREBRAL HEMORRHAGES

Intracerebral hemorrhage (ICH) possibly induces damage to surrounding cerebral tissue by ischaemia which may cause severe neurological sequelae, mainly cerebral paresis.Methods: We have measured regional CBF within the first days after diagnosis (1-3days) in 6 preterm infants (GA 26-29weeks) with unilateral ICH and in 9 preterm infants (GA 26-32weeks) without ICH using single photon emission computer tomography and 99mTc-HMPAO (Ceretec®) i a dose of 4MBq/kg. We used a 4-head fast rotating gamma camera (Tomomatic 248®) with a spatial resolution of 6×6×8mm.Results: Compared to the control group the flow to the white matter of the affected hemisphere was decreased 37% (p=0.0003, non-paired t-test). The flow to the other regions did not differ significantly but the flow to the grey matter of both hemispheres and to the basal ganglia of the affected hemisphere showed a higher variation than the control group (p<0.01, F-test).Conclusion: Similar to former studies in premature infants we have demonstrated a decreased white matter flow in the affected hemisphere. In contrast, flow abnormalities was seen in the grey matter of both hemispheres. This indicates that ICH may be a part of a more widespred brain damage and; may explain the variation in neurological outcome.