Rosa Maria Cerbo

Correlation between cord blood, perinatal BNP values and echocardiographic parameters in healthy Italian newborns.

We evaluated the correlation between brain natriuretic peptide (BNP) in umbilical cord blood after normal pregnancy, in blood samples of twenty-nine Italian healthy newborns and paired echocardiographic parameters. Plasma BNP was evaluated in UCB (T0) and in blood on day 3 (T1), 30 (T2) of life. Echocardiographic parameters were recorded at T1 and T2. Median of BNP concentrations in cord blood was 8.6 pg/ml. Median BNP concentrations on T1 was 59.2 pg/ml, on T2 was 8.7 pg/ml. Significantly higher BNP concentrations were reported on T1 than T0 and T2 (p<0.0001), while no significant difference resulted between T0 and T2. Plasma BNP at T2 was significantly correlated with mVTI (p=0.006), E wave (p=0.004), LA (p=0.047), LVPW (p=0.004), M (p=0.025). No correlation was found with SF% and E/A. Our results confirm that in healthy and term neonates the cord blood BNP concentrations are low. On T1 BNP values are high with wide ranges because of physiological adjustment to postnatal circulation. When echocardiographic parameters are in normal ranges, BNP concentrations return to low levels on day 30. In healthy newborns left ventricular filling, LA size and M seem to influence BNP levels rather than left ventricular systolic and diastolic function.

Cord blood, perinatal BNP values in term and preterm newborns

The number of studies about B-type natriuretic peptide (BNP) and neonates is growing; nevertheless, the use of BNP needs to be further investigated in preterm newborns.1 2 We observed the pattern of plasma BNP concentrations from late fetal life, from umbilical cord blood (UBC) samples, through day 1 of life (preterm only), day 3, and until the first month of life in 32 preterm newborns and 32 full-term healthy newborns. The results are summarised below. Median preterm newborns’ BNP concentrations: UBC, 31 pg/ml (interquartile range (IQR): 7.2–98.6); birth day, 84.4 pg/ml (IQR: 30.6–471.5); day 3, 35.7 pg/ml (IQR: 14.2–119.7); day 30, 12.7 pg/ml (IQR: 5–16.2). Median full-term newborns’ BNP concentrations: UCB, 10.6 …

Cerebral Oxygenation, Superior Vena Cava Flow, Severe Intraventricular Hemorrhage and Mortality in 60 Very Low Birth Weight Infants.

Background: Brain vulnerability in the critically ill preterm newborn may be related to the burden of cerebral hypoxygenation and hypoperfusion during the immediate postnatal period. Objective: We determined the association between adverse outcomes [death or high grade intraventricular hemorrhage (IVH)] and continuous cerebral tissue oxygen saturation (rSO2), superior vena cava flow (SVCf) and cerebral fractional oxygen extraction (CFOE) in very low birth weight (VLBW) infants during the first 48 h of life. Methods: We studied a prospective cohort of 60 VLBW infants admitted to our neonatal intensive care unit within the first 6 h of life between March 2010 and June 2012. rSO2 (expressed as a number of summary measures) was continuously monitored with near-infrared spectroscopy (INVOS 5100 Somanetic) during the first 48 h of life, SCVf was measured at 4-6, 12, 24 and 48 h after birth, and CFOE was calculated. Results: The mean gestational age was 27.9 (SD 2.39); 8 infants died (13.3%) and 7 developed IVH grade III-IV: 1 in the alive group and 6 in the deceased group (p < 0.001). The odds ratio for death was 1.08 (95% CI: 1.015-1.15, p = 0.016) for each 10 periods of rSO2 values <40% in the first 48 h, and 4.2 (95% CI: 1.27-14.05, p = 0.019) for SVCf values <40 ml/kg/min. Among alive babies, mean CFOE decreased at 24, 36 and 48 h; among deceased babies it did not (p < 0.001). In the multivariate analyses, these results retained significance. Conclusions: Both rSO2 ≤40% and SVCf <40 ml/kg/min independently increase the risk of death. The trend in CFOE supports the ischemic-hypoperfusion hypothesis as a mechanism for cerebral damage.

From apneic spells to the development of hypertensive hydrocephalus: a case report of homocystinuria with early onset.

Homocystinuria represents a group of hereditary metabolic disorders characterized by an accumulation of homocysteine in the serum and an increased excretion of homocysteine in the urine. The infantile form is severe: the main clinical findings are neurologic signs, associated with hematological signs and bone alterations. Immediate restoration of plasma amino acids is the primary goal and early diagnosis is crucial not to delay the onset of possible treatment. We report a case of homocystinuria with early onset: an initial symptomatology was undervalued by the pediatrician with a delay in diagnosis. Despite the therapy, the patient developed tetraventricular hydrocephalus requiring ventricular drainage. In conclusion, we want to remember the necessity to perform a complete metabolic workup in a patient with clinical manifestations suggestive for homocystinuria, and the importance of early recognition of the signs and symptoms of hypertensive hydrocephalus, a possible complication of this condition.

Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts

Significance We report the discovery of complete human interleukin-1 receptor (IL-1R)-associated kinase 1 (IRAK-1) deficiency resulting from a de novo Xq28 microdeletion encompassing MECP2 and IRAK1 in a boy. Like many boys with MECP2 defects, this patient died very early. IRAK-1 is a component of the Toll-like receptor (TLR)/IL-1R (TIR) signaling pathway. Unlike patients with autosomal-recessive complete deficiency of MyD88 or IRAK-4, two other components of the TIR pathway, this patient presented no invasive bacterial infections. We analyzed the impact of human IRAK-1 deficiency in fibroblasts and leukocytes. The role of IRAK-1 in signaling downstream from IL-1R and TLRs differed according to cell type. These findings reveal similarities and differences in the role of IRAK-1 in the TLR and IL-1R pathways between mice and humans. Most members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) families transduce signals via a canonical pathway involving the MyD88 adapter and the interleukin-1 receptor-associated kinase (IRAK) complex. This complex contains four molecules, including at least two (IRAK-1 and IRAK-4) active kinases. In mice and humans, deficiencies of IRAK-4 or MyD88 abolish most TLR (except for TLR3 and some TLR4) and IL-1R signaling in both leukocytes and fibroblasts. TLR and IL-1R responses are weak but not abolished in mice lacking IRAK-1, whereas the role of IRAK-1 in humans remains unclear. We describe here a boy with X-linked MECP2 deficiency-related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1. Like many boys with MECP2 null mutations, this child died very early, at the age of 7 mo. Unlike most IRAK-4– or MyD88-deficient patients, he did not suffer from invasive bacterial diseases during his short life. The IRAK-1 protein was completely absent from the patient’s fibroblasts, which responded very poorly to all TLR2/6 (PAM2CSK4, LTA, FSL-1), TLR1/2 (PAM3CSK4), and TLR4 (LPS, MPLA) agonists tested but had almost unimpaired responses to IL-1β. By contrast, the patient’s peripheral blood mononuclear cells responded normally to all TLR1/2, TLR2/6, TLR4, TLR7, and TLR8 (R848) agonists tested, and to IL-1β. The death of this child precluded long-term evaluations of the clinical consequences of inherited IRAK-1 deficiency. However, these findings suggest that human IRAK-1 is essential downstream from TLRs but not IL-1Rs in fibroblasts, whereas it plays a redundant role downstream from both TLRs and IL-1Rs in leukocytes.

A newborn with double-outlet right ventricle and aortopulmonary window associated with maternal phenylketonuria: A first case report

Sir, We report the case of a preterm (36 weeks of gestation), small for gestational age male newborn affected of microcephaly and of a complex congenital heart defect (CHD) including double outlet right ventricle (DORV) with subaortic ventricular defect, right lateral aorta, subaortic and subpulmonary conuses, and pulmonary stenosis (type II DORV according to the classification system proposed by Van Praagh and colleagues (1). The patient also presented aortopulmonary window (APW) between the ascending aorta and the main pulmonary artery (type I APW according to the classification system proposed by Richardson and colleagues (2). A successful repair of the APW was performed at 1 week of life by closing the window with ligation through a median sternotomy. A complete repair of DORV was carried out with success at 5 months of age. The surgical correction consisted of creation of an intraventricular tunnel between the ventricular septal defect and the subaortic outflow tract; the right ventricular outflow tract was enlarged by infundibular resection and placement of a pericardial patch. Caryotype and fluorescence in situ hybridization was performed and excluded chromosomal abnormalities or deletions on the long arm of chromosome 22. Because of the clinical features of the children, maternal serum phenylalanine concentration was analysed and the mother resulted to be affected of phenylketonuria (PKU). Aortopulmonary window represents a failure of the conotruncus to differentiate into the aorta and pulmonary artery. No genetic associations or environmental risk factors are known. In contrast to other major CHDs, there are no systematic or comprehensive data regarding associations, aetiologies, and pathogenesis of DORV and this condition remains one of the least understood categories of CHD. DORV may occur as an isolated cardiac defect, together with other cardiac lesions, or in association with extracardiac anomalies. A variety of chromosomal abnormalities were noted in the cases of DORV reported in literature, comprising slightly <41% of reported cases (3). Many non-chromosomal syndromes have also been associated with DORV and comprised over 56% of the cases reported in literature (3). There are few data associating human DORV with teratogenic exposures; only about 3% of the cases reported in the literature appeared to have a possible teratogenic association (3). To our knowledge, no association is reported in literature between DORV or APW and maternal PKU (MPKU). The most frequent cardiac defects associated with MPKU are tetralogy of Fallot, ventricular septal defects, patent ductus arteriosus and single ventricle. This report supports the hypothesis that type II DORV and APW might reflect abnormal genetically programmed or teratogen-induced maldevelopment of the endocardial cushions crucial in atrioventricular and semilunar valve formation, also affecting portions of the conal and ventricular septum of the heart. Additional human and animal studies are needed to further define genetic and nongenetic aetiologies and pathogenetic mechanisms of DORV and APW. This information will be important to define the natural histories of different causes of DORV and APW, and to accurately define the associated reproductive recurrence risks.

Cerebral Arteriovenous Shunts Regression in Two Preterm Newborns with Heart Failure in Utero

In this report, the cases of two newborn infants with cerebral arteriovenous shunts and heart failure in utero are presented. Different from the malformations of the vein of Galen, which usually generate a progressive and lethal heart failure after birth, our cases show heart failure resolution after birth, together with cerebral vascular shunt disappearance. Therefore, we hypothesized that the opening of arteriovenous shunts was a secondary modification due to the intrauterine heart failure. From our cases, it appears that, despite the dramatic echographic appearance, generalized cerebral venous dilatation can resolve spontaneously without sequelae.

Near-Infrared Spectroscopy Monitoring, Superior Vena Cava Flow, and Neurodevelopmental Outcome at 2 years in a Cohort of Very Low-Birth-Weight Infants.

Objective We aimed at assessing the association between superior vena cava flow (SVCf), regional (cerebral) tissue oxygen saturation (rSO2), and cerebral fractional oxygen extraction (CFOE) during the first 48 hours of life and 2-years neurodevelopmental outcome of very low-birth-weight infants (VLBW). Methods We prospectively studied 60 VLBW infants admitted to our neonatal intensive care unit; rSO2 was continuously monitored with near-infrared spectroscopy during the first 48 hours of life, SVCf was measured at 4 to 6, 12, 24, and 48 hours, and CFOE was calculated. Neurodevelopmental outcome was assessed at 24 months corrected age. Results The mean gestational age at birth was 27.9 weeks (standard deviation: 2.4); 8 infants died in the first 3 months of life, 6 were lost to follow-up, 46 survived and were followed up. At 24 months, 6 (13%) and 7 (15.2%) infants developed minor and major sequelae, respectively. Infants who died had higher CFOE (p < 0.001) and lower SVCf (p < 0.001) than infants surviving with sequelae. In turn, these had higher SVCf between 24 and 48 hours than those without sequelae (p < 0.001). Conclusion SVCf, rSO2, and CFOE patterns in the first days of life suggest cerebral hyperperfusion, related to loss of autoregulation and/or use of inotropic drugs, as a potential mechanism of cerebral injury.

Contents Vol. 108, 2015

K. Allegaert, Leuven S. Andersson, Helsinki E. Bancalari, Miami, Fla. D. Bassler, Zurich J. Bhatia, Augusta, Ga. C. Bührer, Berlin W. Carlo, Birmingham, Ala. R. Christensen, Salt Lake City, Utah T. Curstedt, Stockholm C. Dani, Florence B. Darlow, Christchurch M. Hallman, Oulu W.W. Hay, Jr., Aurora, Colo. S.E. Juul, Seattle, Wash. M. Kaplan, Jerusalem B. Kramer, Maastricht R.J. Martin, Cleveland, Ohio C.J. Morley, Cambridge J. Neu, Gainesville, Fla. P.C. Ng, Hong Kong M.W. Obladen, Berlin W.S. Park, Seoul A.G.S. Philip, Sebastopol, Calif. M. Roth-Kleiner, Lausanne E. Saliba, Tours O.D. Saugstad, Oslo M.S. Schimmel, Jerusalem M.P. Sherman, Columbia, Mo. E.S. Shinwell, Tsfat K. Simmer, Perth, W.A. J. Smith, Tygerberg R.F. Soll, Burlington, Vt. (Cochrane Review Updates) B. Sun, Shanghai N. Takahashi, Tokyo N. Vain, Buenos Aires F. van Bel, Utrecht J.N. van den Anker, Washington, D.C. M. Vento Torres, Valencia F.J. Walther, Leiden M. Weindling, Liverpool J.A. Widness, Iowa City, Iowa T.F. Yeh, Taipei Fetal and Neonatal Research

Hemodynamically significant ductus arteriosus:a new targeted approach

Debate on hemodynamically significant ductusarteriosus (hsDA) in premature infants remains unresolved. The association between patent ductus arteriosus (PDA) and the most adverse outcomes and comorbidities in preterms (peri-intraventricular haemorrhage, necrotizing enterocolitis, chronic lung disease, pulmonary haemorrhage and mortality) has led to the integration of ductal closure into neonatal intensive care. The recent theory that describes PDA as “an innocent bystander” is supported by the lack of evidence of significant benefits on long-term outcomes with therapeutic interventions. So, the causal relationship between PDA and comorbidities is questioned. Moreover, PDA can close spontaneously in a significant proportion of preterms[1]. Both the traditional assumption that all PDA are pathological and the most recent theory in favor of a conservative attitudeare oversimplifications[2]. The current management of PDA does not take into account the wide range of effects attributable to a ductal shunt. A more logical approach should considerthe ductus as a clinical continuum, from thephysiological PDA to the pathological hsDA. Placingthe patient in the spectrum of “ductal disease” seems to be possible through a continuous evaluation of the hemodynamic and clinical consequences of ductal patency[3]. The current definition of an hsDA is almost entirely based on size[4]. However, the magnitude of transductal shunt relates not only to the transductal diameter, but also to the pulmonary and systemic vascular resistance and to the compensatory ability of the immature myocardium[3]. New echocardiography markers have been evaluated to estimate the impact of transductal flow on both pulmonary over circulation (left atrial/aortic ratio, anterograde pulmonary artery diastolic flow) and systemic blood flow (retrograde diastolic flow in descending aorta, left ventricular output/superior vena cava flow ratio)[5]. The possibility to evaluate flows in the middle cerebral artery, renaland superior mesenteric artery with Doppler ultrasound, allows anearly and plausible detection of regional hypoperfusion due to the “ductal steal”[3]. Other technologies that enable direct measurement of tissue oxygenation, such as Near Infrared Spectroscopy (NIRS), may also be useful to unveil the hemodynamic effects of PDA[6,7]. We are becoming increasingly aware of the role of patients characteristics (such as genetic profile[8], BNP levels[9], antioxidant status[10]) in PDA evolution. According to the current understanding, it seems appropriate to proposea more tailored approach to the management of PDA in preterms, based on the integration between clinical and hemodynamic status.