Matthew Borzage

Hemodynamic monitoring in neonates: advances and challenges.

Continuous, reliable and real-time assessment of major determinants of cardiovascular function in preterm and term neonates has long been an elusive aim in neonatal medicine. Accordingly, aside from continuous assessment of heart rate, blood pressure and arterial oxygen saturation, bedside monitoring of major determinants of cardiovascular function of significant clinical relevance such as cardiac output, systemic vascular resistance, organ blood flow distribution and tissue oxygen delivery and coupling has only recently become available. Without obtaining reliable information on the changes in and interactions among these parameters in the neonatal patient population during postnatal transition and later in the neonatal period, development of effective and less harmful treatment approaches to cardiovascular compromise is not possible. This paper briefly reviews the recent advances in our understanding of developmental cardiovascular physiology and discusses the methods of bedside assessment of cardiovascular function in general and organ perfusion, tissue oxygen delivery and brain function in particular in preterm and term neonates. The importance of real-time data collection and the need for meticulous validation of the methods recently introduced in the assessment of neonatal cardiovascular function such as echocardiography, electrical impedance cardiometry, near infrared spectroscopy, visible light and laser-Doppler technology are emphasized. A clear understanding of the accuracy, feasibility, reliability and limitations of these methods through thorough validation will result in the most appropriate usage of these methods in clinical research and patient care.

Current and emerging MR imaging techniques for the diagnosis and management of CSF flow disorders: a review of phase-contrast and time-spatial labeling inversion pulse.

SUMMARY: This article provides an overview of phase-contrast and time–spatial labeling inversion pulse MR imaging techniques to assess CSF movement in the CNS under normal and pathophysiologic situations. Phase-contrast can quantitatively measure stroke volume in selected regions, notably the aqueduct of Sylvius, synchronized to the heartbeat. Judicious fine-tuning of the technique is needed to achieve maximal temporal resolution, and it has limited visualization of CSF motion in many CNS regions. Phase-contrast is frequently used to evaluate those patients with suspected normal pressure hydrocephalus and a Chiari I malformation. Correlation with successful treatment outcome has been problematic. Time–spatial labeling inversion pulse, with a high signal-to-noise ratio, assesses linear and turbulent motion of CSF anywhere in the CNS. Time–spatial labeling inversion pulse can qualitatively visualize whether CSF flows between 2 compartments and determine whether there is flow through the aqueduct of Sylvius or a new surgically created stoma. Cine images reveal CSF linear and turbulent flow patterns.

Basic Principles and Concepts Underlying Recent Advances in Magnetic Resonance Imaging of the Developing Brain

Over the last decade, magnetic resonance (MR) imaging has become an essential tool in the evaluation of both in vivo human brain development and perinatal brain injury. Recent technology including MR-compatible neonatal incubators, neonatal head coils, advanced MR pulse sequences, and 3-T field strength magnets allow high-quality MR imaging studies to be performed on sick neonates. This article will review basic principles and concepts underlying recent advances in MR spectroscopy, diffusion, perfusion, and volumetric MR imaging. These techniques provide quantitative assessment and novel insight of both brain development and brain injury in the immature brain. Knowledge of normal developmental changes in quantitative MR values is also essential to interpret pathologic cases.

Dose-Dependent Hemodynamic and Metabolic Effects of Vasoactive Medications in Normotensive, Anesthetized Neonatal Piglets

The developmentally regulated hemodynamic effects of vasoactive medications have not been well characterized. We used traditional and near-infrared spectroscopy monitoring technologies and investigated the changes in heart rate, blood pressure, common carotid artery (CCA) blood flow (BF), cerebral, renal, intestinal, and muscle regional tissue O2 saturation, and acid-base and electrolyte status in response to escalating doses of vasoactive medications in normotensive anesthetized neonatal piglets. We used regional tissue O2 saturation and CCA BF as surrogates of organ and systemic BF, respectively, and controlled minute ventilation and oxygenation. Low to medium doses of dopamine, epinephrine, dobutamine, and norepinephrine increased blood pressure and systemic and regional BF in a drug-specific manner, whereas milrinone exerted minimal effects. At higher doses, dopamine, epinephrine, and norepinephrine but not dobutamine decreased systemic, renal, intestinal, and muscle BF, while cerebral BF remained unchanged. Epinephrine induced significant increases in muscle BF and serum glucose and lactate concentrations. The findings reveal novel drug- and dose-specific differences in the hemodynamic response to escalating doses of vasoactive medications in the neonatal cardiovascular system and provide information for future clinical studies investigating the use of vasoactive medications for the treatment of neonatal cardiovascular compromise.

Determinants of resting cerebral blood flow in sickle cell disease

Stroke is common in children with sickle cell disease and results from an imbalance in oxygen supply and demand. Cerebral blood flow (CBF) is increased in patients with sickle cell disease to compensate for their anemia, but adequacy of their oxygen delivery has not been systematically demonstrated. This study examined the physiological determinants of CBF in 37 patients with sickle cell disease, 38 ethnicity matched control subjects and 16 patients with anemia of non‐sickle origin. Cerebral blood flow was measured using phase contrast MRI of the carotid and vertebral arteries. CBF increased inversely to oxygen content (r2 = 0.69, P < 0.0001). Brain oxygen delivery, the product of CBF and oxygen content, was normal in all groups. Brain composition, specifically the relative amounts of grey and white matter, was the next strongest CBF predictor, presumably by influencing cerebral metabolic rate. Grey matter/white matter ratio and CBF declined monotonically until the age of 25 in all subjects, consistent with known maturational changes in brain composition. Further CBF reductions were observed with age in subjects older than 35 years of age, likely reflecting microvascular aging. On multivariate regression, CBF was independent of disease state, hemoglobin S, hemoglobin F, reticulocyte count and cell free hemoglobin, suggesting that it is regulated similarly in patients and control subjects. In conclusion, sickle cell disease patients had sufficient oxygen delivery at rest, but accomplish this only by marked increases in their resting CBF, potentially limiting their ability to further augment flow in response to stress. Am. J. Hematol. 91:912–917, 2016.

Neonatal hemodynamics: monitoring, data acquisition and analysis

Monitoring of cardiovascular function is critical to both clinical care and research as the use of sophisticated monitoring systems enable us to obtain accurate, reliable and real-time information on developmental hemodynamics in health and disease. Novel approaches to comprehensive hemodynamic monitoring and data acquisition will undoubtedly aid in developing a better understanding of developmental cardiovascular physiology in neonates. In addition, development and use of state-of-the-art, comprehensive hemodynamic monitoring systems enable the recognition of signs of cardiovascular compromise in its early stages, and provide information on the hemodynamic response to treatment in critically ill patients.

Predictors of cerebral blood flow in patients with and without anemia.

Sickle cell disease (SCD) is the most common cause of stroke in childhood and results primarily from a mismatch of cerebral oxygen supply and demand rather than arterial obstruction. However, resting cerebral blood flow (CBF) has not been examined in the general African American population, in whom obesity, hypertension, cerebrovascular disease, and diminished cerebrovascular reserve capacity are common. To better understand the underlying physiological substrate upon which SCD is superimposed, we measured CBF in 32 young (age 28 ± 10 yr), asymptomatic African American subjects with and without sickle cell trait (n= 14). To characterize the effects of chronic anemia, in isolation of sickle hemoglobin we also studied a cohort of 13 subjects with thalassemia major (n= 10), dyserythropoetic anemia (n= 1), or spherocytosis (n= 2). Blood was analyzed for complete blood count, hemoglobin electrophoresis, cell free hemoglobin, and lactate dehydrogenase. Multivariate regression analysis showed that oxygen content was the strongest predictor of CBF (r(2)= 0.33,P< 0.001). CBF declined rapidly in the second and third decades of life, but this drop was explained by reductions in cerebral gray matter. However, age effects persisted after correction for brain composition, possibly representing microvascular impairment. CBF was independent of viscosity, hemoglobin S%, and body mass index. Hyperoxia resulted in reduced CBF by 12.6% (P= 0.0002), and CBF changes were proportional to baseline oxygen content (r(2)= 0.16,P= 0.02). These data suggest that these hemoglobin subtypes do not alter the normal CBF regulation of the balance of oxygen supply and demand.

Empirical model of human blood transverse relaxation at 3 T improves MRI T2 oximetry.

We sought a human blood T2‐oximetery calibration curve over the wide range of hematocrits commonly found in anemic patients applicable with T2 relaxation under spin tagging (TRUST).

Hemoglobin and mean platelet volume predicts diffuse T1-MRI white matter volume decrease in sickle cell disease patients

Sickle cell disease (SCD) is a life-threatening genetic condition. Patients suffer from chronic systemic and cerebral vascular disease that leads to early and cumulative neurological damage. Few studies have quantified the effects of this disease on brain morphometry and even fewer efforts have been devoted to older patients despite the progressive nature of the disease. This study quantifies global and regional brain volumes in adolescent and young adult patients with SCD and racially matched controls with the aim of distinguishing between age related changes associated with normal brain maturation and damage from sickle cell disease. T1 weighted images were acquired on 33 clinically asymptomatic SCD patients (age = 21.3 ± 7.8; F = 18, M = 15) and 32 racially matched control subjects (age = 24.4 ± 7.5; F = 22, M = 10). Exclusion criteria included pregnancy, previous overt stroke, acute chest, or pain crisis hospitalization within one month. All brain volume comparisons were corrected for age and sex. Globally, grey matter volume was not different but white matter volume was 8.1% lower (p = 0.0056) in the right hemisphere and 6.8% (p = 0.0068) in the left hemisphere in SCD patients compared with controls. Multivariate analysis retained hemoglobin (β = 0.33; p = 0.0036), sex (β = 0.35; p = 0.0017) and mean platelet volume (β = 0.27; p = 0.016) as significant factors in the final prediction model for white matter volume for a combined r2 of 0.37 (p < 0.0001). Lower white matter volume was confined to phylogenetically younger brain regions in the anterior and middle cerebral artery distributions. Our findings suggest that there are diffuse white matter abnormalities in SCD patients, especially in the frontal, parietal and temporal lobes, that are associated with low hemoglobin levels and mean platelet volume. The pattern of brain loss suggests chronic microvascular insufficiency and tissue hypoxia as the causal mechanism. However, longitudinal studies of global and regional brain morphometry can help us give further insights on the pathophysiology of SCD in the brain.

Cerebral Lactate Concentration in Neonatal Hypoxic-Ischemic Encephalopathy: In Relation to Time, Characteristic of Injury, and Serum Lactate Concentration

Background Cerebral lactate concentration can remain detectable in neonatal hypoxic-ischemic encephalopathy (HIE) after hemodynamic stability. The temporal resolution of regional cerebral lactate concentration in relation to the severity or area of injury is unclear. Furthermore, the interplay between serum and cerebral lactate in neonatal HIE has not been well defined. The study aims to describe cerebral lactate concentration in neonatal HIE in relation to time, injury, and serum lactate. Design/methods Fifty-two newborns with HIE undergoing therapeutic hypothermia (TH) were enrolled. Magnetic resonance imaging and spectroscopy (MRI + MR spectroscopy) were performed during and after TH at 54.6 ± 15.0 and 156 ± 57.6 h of life, respectively. Severity and predominant pattern of injury was scored radiographically. Single-voxel 1H MR spectra were acquired using short-echo (35 ms) PRESS sequence localized to the basal ganglia (BG), thalamus (Thal), gray matter (GM), and white matter. Cerebral lactate concentration was quantified by LCModel software. Serum and cerebral lactate concentrations were plotted based on age at time of measurement. Multiple comparisons of regional cerebral lactate concentration based on severity and predominant pattern of injury were performed. Spearman’s Rho was computed to determine correlation between serum lactate and cerebral lactate concentration at the respective regions of interest. Results Overall, serum lactate concentration decreased over time. Cerebral lactate concentration remained low for less severe injury and decreased over time for more severe injury. Cerebral lactate remained detectable even after TH. During TH, there was a significant higher concentration of cerebral lactate at the areas of injury and also when injury was more severe. However, these differences were no longer observed after TH. There was a weak correlation between serum lactate and cerebral lactate concentration at the BG (rs = 0.3, p = 0.04) and Thal (rs = 0.35, p = 0.02). However, in infants with moderate–severe brain injury, a very strong correlation exists between serum lactate and cerebral lactate concentration at the BG (rs = 0.7, p = 0.03), Thal (rs = 0.9 p = 0.001), and GM (rs = 0.6, p = 0.04) regions. Conclusion Cerebral lactate is most significantly different between regions and severity of injury during TH. There is a moderate correlation between serum and cerebral lactate concentration measured in the deep gray nuclei during TH. Differences in injury and altered regional cerebral metabolism may account for these differences.