Cerebral Oximetry Monitoring in Extremely Preterm Infants.

BACKGROUND: The use of cerebral oximetry monitoring in the care of extremely preterm infants is increasing. However, evidence that its use improves clinical outcomes is lacking. METHODS: In this randomized, phase 3 trial conducted at 70 sites in 17 countries, we assigned extremely preterm infants (gestational age, <28 weeks), within 6 hours after birth, to receive treatment guided by cerebral oximetry monitoring for the first 72 hours after birth or to receive usual care. The primary outcome was a composite of death or severe brain injury on cerebral ultrasonography at 36 weeks' postmenstrual age. Serious adverse events that were assessed were death, severe brain injury, bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and late-onset sepsis. RESULTS: A total of 1601 infants underwent randomization and 1579 (98.6%) were evaluated for the primary outcome. At 36 weeks' postmenstrual age, death or severe brain injury had occurred in 272 of 772 infants (35.2%) in the cerebral oximetry group, as compared with 274 of 807 infants (34.0%) in the usual-care group (relative risk with cerebral oximetry, 1.03; 95% confidence interval, 0.90 to 1.18; P = 0.64). The incidence of serious adverse events did not differ between the two groups. CONCLUSIONS: In extremely preterm infants, treatment guided by cerebral oximetry monitoring for the first 72 hours after birth was not associated with a lower incidence of death or severe brain injury at 36 weeks' postmenstrual age than usual care. (Funded by the Elsass Foundation and others; SafeBoosC-III ClinicalTrials.gov number, NCT03770741.).

Infants with Down syndrome and congenital heart disease have altered peri-operative immune responses.

BACKGROUND: Infants with Down syndrome (DS) have an altered immune response. We aimed to characterise the inflammatory response in infants with DS and congenital heart disease (CHD) peri-operatively in comparison to infants with CHD and a normal chromosomal complement, and to healthy infants pre-operatively. METHODS: Infants with DS/CHD, infants without DS but with CHD (CHD only) and healthy infants were prospectively recruited and serial serum cytokines evaluated peri-operatively using multiplex ELISA: tumour necrosis factor (TNF)-α and TNF-ß; interferon (IFN)-γ, interleukin (IL)-1α, IL-2, IL-6, IL-8, IL-18, IL-1ß, IL-10, and IL-1ra; vascular endothelial growth factor (VEGF); granulocyte macrophage colony-stimulating factor (GM-CSF); and erythropoietin (EPO). RESULTS: Ninety-four infants were recruited including age-matched controls (n = 10), DS/CHD (n = 55), and CHD only (n = 29). Children with DS/CHD had significantly lower concentrations of several cytokines (IL-10, IL-6, IL-8, IL-1ß, VEGF) in the pre- and post-operatively vs CHD only and controls. EPO and GM-CSF were significantly higher in DS/CHD (p value <0.05). CONCLUSIONS: Children with DS/CHD had significantly lower concentrations of several cytokines compared to controls or children with CHD only. EPO and GM-CSF were significantly higher in children with DS/CHD. The assessment of the immune response may be suitable for the predictable clinical outcomes in these children. IMPACT: This study demonstrated that children with Down syndrome (DS) and congenital heart disease (CHD) have significant alterations in pro-inflammatory and anti-inflammatory immune responses peri-operatively. These changes may contribute to adverse clinical outcomes, including sepsis, chylothorax, and autoimmunity. They may impact the pathogenesis and outcome post-operatively and long term in this population. Children with DS and CHD have significantly lower cytokine concentrations, increased EPO and GM-CSF, and decreased VEGF pre- and post-operatively. Assessing their inflammatory state peri-operatively may facilitate the development of a predictive model that can inform tailored management of these infants using novel therapies including immunomodulation.

Altered Cytokine Endotoxin Responses in Neonatal Encephalopathy Predict MRI Outcomes.

Background: Neonatal encephalopathy (NE) is associated with adverse neurodevelopmental outcome and is linked with systemic inflammation. Pro-inflammatory and anti-inflammatory cytokines are known to play a role in the pathology of NE by activating innate immune cells. Methods: Eighty-seven infants were enrolled including 53 infants with NE of whom 52 received therapeutic hypothermia (TH) and 34 term infant healthy controls (TC). Whole blood sampling was performed in the first 4 days of life, and a 14-spot ELISA Multiplex Cytokine Array was carried out on baseline samples or after stimulation with lipopolysaccharide (LPS) as an additional inflammatory stimulus. The cytokine medians were examined for differences between infants with NE and healthy TC; and then short-term outcomes of Sarnat stage, seizures, and MRI brain were examined within the NE group. The potential of LPS stimulation to predict abnormal MRI was explored using receiver operating characteristic (ROC) curves. Results: At baseline, infants with NE had significantly higher levels of erythropoietin (Epo), interleukin (IL)-6, and IL-1ra and significantly lower vascular endothelial growth factor (VEGF) than had controls. All cytokines were increased after LPS stimulation in infants with NE with an excessive Epo and IL-1ra response than in controls. Infants with NE had lower IL-8, IL-2, IL-6, tumor necrosis factor (TNF)-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), VEGF, and interferon (IFN)-γ than controls had following LPS. GM-CSF and IFN-γ, IL-1ß, IL-1ra, and VEGF were higher on days 1-2 in NE infants with abnormal neuroimaging. GM-CSF, IFN-γ, and TNF-α levels with LPS stimulation were different upon stimulation between normal and abnormal neuroimaging. TNF-α is the only strong cytokine predictor both pre- and post-LPS stimulation of abnormal brain imaging. Conclusions: Altered cytokine responses are found in infants with NE vs. controls, and more significant differences are unmasked by the additional stimulus of LPS, which potentially improves the predictive power of these cytokines for the detection of abnormal MRIs. Infants with NE undergoing TH demonstrate both trained immunity and tolerance, and understanding these responses will facilitate adjunctive immunomodulatory treatments.

Left Ventricle Phenotyping Utilizing Tissue Doppler Imaging in Premature Infants with Varying Severity of Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is characterized by alveolar-capillary simplification and is associated with pulmonary hypertension (PH) in preterm infants. The contribution of left ventricle (LV) disease towards this severe BPD-PH phenotype is not well established. We aimed to describe the longitudinal trajectory of the LV function as measured by tissue Doppler imaging (TDI) and its association with BPD-PH. We retrospectively assessed prospectively acquired clinical and echocardiographic data from 77 preterm infants born between 2011 and 2013. We characterized the LV function by measuring systolic and diastolic myocardial velocities (s', e', a'), isovolumetric relaxation time (IVRT), and myocardial performance index with TDI at three time periods from 32 and 36 weeks, postmenstrual age through one year of age. We also measured post systolic motion (PSM), a marker of myocardial dysfunction that results from asynchronous movement of the ventricular walls, and not previously described in preterm infants. Patients were stratified into groups according to BPD severity and the presence of PH and compared over time. Conventional TDI measures of the LV function were similar between groups, but the septal PSM was significantly prolonged over the first year of age in patients with BPD-PH. PSM provides a novel objective way to assess the hemodynamic impact of lung and pulmonary vascular disease severity on LV function in preterm infants with BPD and PH.

Echocardiographic Assessment of Right Ventricular Afterload in Preterm Infants: Maturational Patterns of Pulmonary Artery Acceleration Time Over the First Year of Age and Implications for Pulmonary Hypertension.

BACKGROUND: Assessment of pulmonary hemodynamics is critical in the diagnosis and management of cardiopulmonary disease of premature infants, but reliable noninvasive indices of pulmonary hemodynamics in preterm infants are lacking. Because pulmonary artery acceleration time (PAAT) is a validated noninvasive method to assess right ventricular (RV) afterload in infants and children, the aim of this study was to investigate the maturational changes of PAAT measures in preterm infants over the first year of age and to discern the impact of typical cardiopulmonary abnormalities on these measures. METHODS: In a prospective multicenter study of 239 preterm infants (<29 weeks at birth), PAAT was assessed at days 1, 2, and 5 to 7, at 32 and 36 weeks' postmenstrual age, and at 1-year corrected age. To account for heart rate variability, PAAT was adjusted for RV ejection time. Premature infants who developed bronchopulmonary dysplasia or had echocardiographic findings of pulmonary hypertension were analyzed separately. Intra- and interobserver reproducibility analysis was performed. RESULTS: PAAT was feasible in 95% of the image acquisitions, and there was high intra- and interobserver agreement (intraclass correlation coefficients > 0.9 and coefficients of variation < 6%). In uncomplicated preterm infants (n = 103 [48%]) PAAT and PAAT adjusted for RV ejection time increased longitudinally from birth to 1-year corrected age (P < .001) and were linearly associated with gestational age at birth (r = 0.81 and r = 0.82, P < .001) and increasing postnatal weight and postnatal age (r > 0.81, P < .001). PAAT measures were significantly reduced (P < .001) in infants with bronchopulmonary dysplasia and/or pulmonary hypertension (n = 119 [51%]) beyond 1 week of age. CONCLUSIONS: PAAT measures increase in preterm infants from birth to 1-year corrected age, reflective of the physiologic postnatal drop in RV afterload. Bronchopulmonary dysplasia and pulmonary hypertension have a negative impact on PAAT measures. By demonstrating excellent reliability and establishing reference patterns of PAAT in preterm infants, this study suggests that PAAT and PAAT adjusted for RV ejection time can be used as complementary parameters to assess physiologic and pathologic changes in pulmonary hemodynamics in neonates.

Application of NPE in the assessment of a patent ductus arteriosus.

In many preterm infants, the ductus arteriosus remains patent beyond the first few days of life. This prolonged patency is associated with numerous adverse outcomes, but the extent to which these adverse outcomes are attributable to the hemodynamic consequences of ductal patency, if at all, has not been established. Different treatment strategies have failed to improve short-term outcomes, with a paucity of data on the correct diagnostic and pathophysiological assessment of the patent ductus arteriosus (PDA) in association with long-term outcomes. Echocardiography is the selected method of choice for detecting a PDA, assessing the impact on the preterm circulation and monitoring treatment response. PDA in a preterm infant can result in pulmonary overcirculation and systemic hypoperfusion, Therefore, echocardiographic assessment should include evaluation of PDA characteristics, indices of pulmonary overcirculation with left heart loading conditions, and indices of systemic hypoperfusion. In this review, we provide an evidence-based overview of the current and emerging ultrasound measurements available to identify and monitor a PDA in the preterm infant. We offer indications and limitations for using Neonatologist Performed Echocardiography to optimize the management of a neonate with a PDA.

Application of Neonatologist Performed Echocardiography in the assessment and management of persistent pulmonary hypertension of the newborn.

Pulmonary hypertension contributes to morbidity and mortality in both the term newborn infant, referred to as persistent pulmonary hypertension of the newborn (PPHN), and the premature infant, in the setting of abnormal pulmonary vasculature development and arrested growth. In the term infant, PPHN is characterized by the failure of the physiological postnatal decrease in pulmonary vascular resistance that results in impaired oxygenation, right ventricular failure, and pulmonary-to-systemic shunting. The pulmonary vasculature is either maladapted, maldeveloped, or underdeveloped. In the premature infant, the mechanisms are similar in that the early onset pulmonary hypertension (PH) is due to pulmonary vascular immaturity and its underdevelopment, while late onset PH is due to the maladaptation of the pulmonary circulation that is seen with severe bronchopulmonary dysplasia. This may lead to cor-pulmonale if left undiagnosed and untreated. Neonatologist performed echocardiography (NPE) should be considered in any preterm or term neonate that presents with risk factors suggesting PPHN. In this review, we discuss the risk factors for PPHN in term and preterm infants, the etiologies, and the pathophysiological mechanisms as they relate to growth and development of the pulmonary vasculature. We explore the applications of NPE techniques that aid in the correct diagnostic and pathophysiological assessment of the most common neonatal etiologies of PPHN and provide guidelines for using these techniques to optimize the management of the neonate with PPHN.

Introduction to neonatologist-performed echocardiography.

Cardiac ultrasound techniques are increasingly used in the neonatal intensive care unit to guide cardiorespiratory care of the sick newborn. This is the first in a series of eight review articles discussing the current status of "neonatologist-performed echocardiography" (NPE). The aim of this introductory review is to discuss four key elements of NPE. Indications for scanning are summarized to give the neonatologist with echocardiography skills a clear scope of practice. The fundamental physics of ultrasound are explained to allow for image optimization and avoid erroneous conclusions from artifacts. To ensure patient safety during echocardiography recommendations are given to prevent cardiorespiratory instability, hypothermia, infection, and skin lesions. A structured approach to echocardiography, with the same standard views acquired in the same sequence at each scan, is suggested in order to ensure that the neonatologist confirms normal structural anatomy or acquires the necessary images for a pediatric cardiologist to do so when reviewing the scan.

Late oral acetaminophen versus immediate surgical ligation in preterm infants with persistent large patent ductus arteriosus.

OBJECTIVE: The study objective was to evaluate the association of oral acetaminophen therapy versus immediate surgical ligation with neonatal outcomes in infants with persistent patent ductus arteriosus. METHODS: We performed a retrospective cohort study of preterm infants born 28+6 weeks or less gestational age with persistent large patent ductus arteriosus being considered for surgical ligation after unsuccessful medical therapy. Infants in epoch 1 (July 2009 to June 2012) were immediately referred for ligation, and infants in epoch 2 (July 2012 to June 2015) were treated with oral acetaminophen and referred for ligation in the absence of improvement. The primary outcome was a composite of death or chronic lung disease. RESULTS: A total of 92 infants with median (interquartile range) gestational age 25.2 weeks (24.4-26.3) had persistent large patent ductus arteriosus (43 in epoch 1, 49 in epoch 2). Infants in epoch 2 had decreased surgical ligation (26 [53%] vs 31 [72%]; adjusted odds ratio [aOR], 0.32; 95% confidence interval [CI], 0.12-0.89) but increased chronic lung disease (36 [73%] vs 25 [58%]; aOR, 3.34; 95% CI, 1.05-10.58) and increased death/chronic lung disease of borderline significance (39 [80%] vs 29 [67%]; aOR, 3.09; 95% CI, 0.99-9.63). Infants in epoch 2 took longer to wean off of positive pressure ventilation (28.5 vs 24 days after enrollment; aOR, 0.52; 95% CI, 0.31-0.85). CONCLUSIONS: Late oral acetaminophen therapy for infants with persistent patent ductus arteriosus is associated with reduced surgical ligation but increased chronic lung disease. In light of a lack of improvement in clinical outcomes, the individual contributory effects of acetaminophen, surgical ligation, and prolonged exposure to patent ductus arteriosus require further study to define the optimal approach.

Maturational Patterns of Systolic Ventricular Deformation Mechanics by Two-Dimensional Speckle-Tracking Echocardiography in Preterm Infants over the First Year of Age.

BACKGROUND: The aim of this study was to determine the maturational changes in systolic ventricular strain mechanics by two-dimensional speckle-tracking echocardiography in extremely preterm neonates from birth to 1 year of age and discern the impact of common cardiopulmonary abnormalities on the deformation measures. METHODS: In a prospective multicenter study of 239 extremely preterm infants (<29 weeks gestation at birth), left ventricular (LV) global longitudinal strain (GLS) and global longitudinal systolic strain rate (GLSRs), interventricular septal wall (IVS) GLS and GLSRs, right ventricular (RV) free wall longitudinal strain and strain rate, and segmental longitudinal strain in the RV free wall, LV free wall, and IVS were serially measured on days 1, 2, and 5 to 7, at 32 and 36 weeks postmenstrual age, and at 1 year corrected age (CA). Premature infants who developed bronchopulmonary dysplasia or had echocardiographic findings of pulmonary hypertension were analyzed separately. RESULTS: In uncomplicated preterm infants (n = 103 [48%]), LV GLS and GLSRs remained unchanged from days 5 to 7 to 1 year CA (P = .60 and P = .59). RV free wall longitudinal strain, RV free wall longitudinal strain rate, and IVS GLS and GLSRs significantly increased over the same time period (P < .01 for all measures). A significant base-to-apex (highest to lowest) segmental longitudinal strain gradient (P < .01) was seen in the RV free wall and a reverse apex-to-base gradient (P < .01) in the LV free wall. In infants with bronchopulmonary dysplasia and/or pulmonary hypertension (n = 119 [51%]), RV free wall longitudinal strain and IVS GLS were significantly lower (P < .01), LV GLS and GLSRs were similar (P = .56), and IVS segmental longitudinal strain persisted as an RV-dominant base-to-apex gradient from 32 weeks postmenstrual age to 1 year CA. CONCLUSIONS: This study tracks the maturational patterns of global and regional deformation by two-dimensional speckle-tracking echocardiography in extremely preterm infants from birth to 1 year CA. The maturational patterns are ventricular specific. Bronchopulmonary dysplasia and pulmonary hypertension leave a negative impact on RV and IVS strain, while LV strain remains stable.

Predictors of respiratory instability in neonates undergoing patient ductus arteriosus ligation after the introduction of targeted milrinone treatment.

INTRODUCTION: The postoperative course of preterm babies undergoing surgical closure of a patent ductus arteriosus (PDA) is often complicated by postligation cardiac syndrome (PLCS). Despite targeted milrinone prophylaxis, some infants continue to experience postoperative respiratory deterioration. Our objective is to describe the immediate postoperative course and identify risk factors for respiratory instability when preterm infants undergoing PDA ligation are managed with targeted milrinone treatment. METHODS: A retrospective review of a cohort of infants undergoing PDA ligation between January, 2010 and August, 2013 was conducted. All infants had a targeted neonatal echocardiogram performed 1 hour after surgery. Infants received prophylactic milrinone treatment if the left ventricular output was <200 mL/kg/min. The primary outcome measure was the development of respiratory instability within 24 hours of surgery. Multivariable logistic regression was performed to identify predictors of respiratory instability. RESULTS: Eighty-six infants with a median gestational age of 25 weeks (interquartile range [IQR], 24-26) and a birth weight of 740 g (IQR, 640-853) were included in this study. Forty-nine (57.0%) received milrinone prophylaxis. There were 44 (51.2%) infants who developed oxygenation or ventilation failure, and 7 (8.1%) neonates developed PLCS. Infants with longer isovolumic relaxation time (IVRT ≥30 milliseconds) were more likely to develop either oxygenation or ventilation failure. CONCLUSIONS: Although the incidence of PLCS has declined after the introduction of targeted milrinone prophylaxis, many preterm infants continue to develop respiratory instability after surgical ligation. In this population, diastolic dysfunction manifested by prolonged IVRT could be associated with an adverse postoperative respiratory course.

Altered hemodynamics and hyperuricemia accompany an elevated sFlt-1/PlGF ratio before the onset of early severe preeclampsia.

OBJECTIVE: Early identification of women at risk of developing early-onset severe preeclampsia (sPE) is a key objective in obstetrics. An elevated ratio of serum soluble fms-like tyrosine kinase (sFlt-1) to placenta-like growth factor (PlGF) (sFlt-1/PlGF ratio) precedes overt hypertension. The longitudinal relationship between this biomarker, maternal hemodynamics, and maternal serum uric acid during the pre-clinical phase is unknown. STUDY DESIGN: We followed 20 normotensive women at high risk of developing sPE from 20 weeks until delivery or 34 weeks' gestation. Non-invasive hemodynamic monitoring using bioreactance technology was performed at 20 to 22, 24 to 26, 28 to 30, and 32 to 34 weeks' gestation. Serum uric acid, sFlt-1, and PlGF were measured simultaneously. RESULTS: Six of 20 women (30%) delivered before 33 weeks with sPE and had significantly higher mean total peripheral resistance (TPR), higher serum uric acid, and higher sFlt-1/PlGF ratios at 24 weeks' gestation than unaffected individuals. The area under the curve, cut-off values, and sensitivity and specificity to predict sPE at 24 weeks were as follows: TPR 0.84, 1250 dyne.s.cm-5, 80%, 93%; sFlt-1/PlGF ratio 0.94, 55, 100%, 93%; and serum uric acid 0.99, 255 µmol/L, 100%, 93%. TPR and sFlt-1 were positively correlated in the sPE group before antihypertensive treatment (r = 0.65, P = 0.01). Serum uric acid correlated with both sFlt-1 (r = 0.65, P = 0.003) and sFlt-1/PlGF ratio (r = 0.54, P = 0.02). CONCLUSION: A combination of non-invasive determination of TPR together with measurement of serum uric acid may identify a subset of clinically high-risk women with evolving sPE, independent of the determination of the sFlt-1/PlGF ratio. The predictive ability of this integrated approach needs to be assessed in a larger cohort of women to further confirm its utility.

Objectifs : L'identification précoce des femmes exposées à des risques d'en venir à présenter une prééclampsie grave d'apparition précoce (PEg) constitue un objectif clé en obstétrique. La constatation d'un rapport sFlt-1 (tyrosine kinase 1 de type fms soluble) - PlGF (facteur de croissance placentaire) (rapport sFlt-1/PlGF) élevé précède celle d'une hypertension patente. La relation longitudinale entre ce marqueur biologique, l'hémodynamique maternelle et le taux sérique maternel d'acide urique au cours de la phase préclinique est inconnue. Devis de l'étude : Nous avons suivi, de 20 semaines jusqu'à l'accouchement ou 34 semaines de gestation, 20 femmes normotendues exposées à un risque élevé d'en venir à présenter une PEg. Un monitorage hémodynamique non effractif (faisant appel à la technologie de la bioréactance) à été mené à 20-22, à 24-26, à 28-30 et à 32-34 semaines de gestation. Les taux sériques d'acide urique, de sFlt-1 et de PlGF ont été mesurés simultanément. Résultats : Six des 20 femmes (30 %) ont accouché avant 33 semaines et présentaient une PEg; elles présentaient une résistance vasculaire périphérique totale (RVPT) moyenne considérablement plus élevée, un taux sérique d'acide urique accru et des rapports sFlt-1/PlGF plus élevés à 24 semaines de gestation que les femmes non affectées. La surface sous la courbe, les valeurs seuils et la sensibilité / spécificité pour ce qui est de la prévision de la PEg à 24 semaines étaient les suivantes : RVPT = 0,84, 1 250 dyne.s.cm-5, 80 %, 93 %; rapport sFlt-1/PlGF = 0,94, 55, 100 %, 93 %; et taux sérique d'acide urique = 0,99, 255 µmol/l, 100 %, 93 %. La RVPT et la sFlt-1 présentaient une corrélation positive au sein du groupe PEg avant la mise en œuvre d'un traitement antihypertenseur (r = 0,65, P = 0,01). Le taux sérique d'acide urique présentait une corrélation tant avec la sFlt-1 (r = 0,65, P = 0,003) qu'avec le rapport sFlt-1/PlGF (r = 0,54, P = 0,02). Conclusion : La combinaison « détermination non effractive de la RVPT-mesure du taux sérique d'acide urique ¼ pourrait permettre l'identification d'un sous-ensemble de femmes qui sont exposées à un risque élevé sur le plan clinique et qui présentent une PEg évolutive, sans devoir avoir recours à la détermination du rapport sFlt-1/PlGF. La valeur prédictive de cette approche intégrée doit être évaluée auprès d'une cohorte de femmes de plus grande envergure afin d'en confirmer davantage l'utilité.

Assessment and treatment of post patent ductus arteriosus ligation syndrome.

OBJECTIVE: To compare differences in tissue Doppler imaging, global longitudinal strain (GLS), and cardiac troponin T (cTnT) between infants with low (<200 mL/kg/min) and high (>200 mL/kg/min) left ventricular (LV) output 1 hour after duct ligation and assess the impact of milrinone treatment on cardiac output and myocardial performance. STUDY DESIGN: LV function was assessed preoperatively and 1 and 18 hours postoperatively. Infants were categorized into a low-output or a normal-output group based on the echocardiographic assessment of LV output at 1 hour. RESULTS: Thirty infants with a mean gestation of 25.3 weeks were enrolled. LV basal lateral S', basal septal S', and basal right ventricular S' were lower in the low-output group (n = 19) at 1 hour postoperatively, with no significant difference in GLS (low-output -10.3% vs high-output -14.4%, P >.05) or cTnT between the groups. Patients in the low-output group were treated with milrinone, and by 18 hours LV performance recovered to levels comparable with the high output group. cTnT values increased at 18 hours in the whole cohort with no significant difference between the groups. CONCLUSION: Tissue Doppler imaging and GLS provide novel insights and further characterization of myocardial performance immediately after patent ductus arteriosus ligation. A reduction in tissue Doppler-derived LV systolic velocity may further help in monitoring cardiac performance after patent ductus arteriosus ligation and for monitoring the effects of treatment.

Adrenal function in preterm infants undergoing patent ductus arteriosus ligation.

BACKGROUND: Targeted milrinone treatment for low left ventricular output (LVO) reduces the incidence of acute cardiorespiratory instability following ligation of patent ductus arteriosus (PDA) in preterm infants. Despite this, some infants continue to experience postoperative deterioration. Adrenal insufficiency related to prematurity has been postulated as a possible mechanism. OBJECTIVES: To describe adrenal function in premature infants undergoing PDA ligation and to investigate its association with pre- and postoperative clinical and echocardiography-derived indices of disease severity. METHODS: A retrospective cohort study was conducted over a 2-year period on infants who underwent PDA ligation and had preoperative adrenocorticotropic hormone (ACTH) stimulation. All infants were screened by echocardiography for low LVO at 1 h after surgery and treated with intravenous milrinone if LVO <200 ml/kg/min. The primary outcome evaluated was low LVO at 1 h after surgery. Secondary outcomes included hypotension and oxygenation and ventilation failure occurring within 24 h. RESULTS: A total of 35 infants at a median gestation of 25.4 (24.5-26.4) weeks and weight at birth of 700 (600-810) g were included. Baseline median cortisol measured preoperatively was 202 (137-403) nmol/l. Following the ACTH stimulation test, 3 infants had cortisol ≤500 nmol/l while 15 had ≤750 nmol/l. There was no association seen between any cortisol value and low LVO postoperatively. Post-ACTH cortisol ≤750 nmol/l was significantly associated with hypotension (p = 0.03) and oxygenation (p = 0.04) and ventilation (p = 0.008) failure. Receiver-operator characteristic curve showed a high predictive value of post-ACTH cortisol for all clinical outcomes. CONCLUSIONS: Post-ACTH cortisol (≤750 nmol/l) may be associated with clinical indices of postoperative cardiorespiratory instability. Relative adrenal insufficiency may play a role in the etiology of post-PDA ligation hemodynamic and respiratory instability.

Acute changes in myocardial systolic function in preterm infants undergoing patent ductus arteriosus ligation: a tissue Doppler and myocardial deformation study.

BACKGROUND: Ligation of a patent ductus arteriosus (PDA) in preterm infants causes profound hemodynamic changes that can result in low cardiac output syndrome and hypotension. The effect of PDA ligation on left ventricular myocardial function has not been studied using tissue Doppler and myocardial deformation imaging, mainly because of the limited validation of these methods in preterm infants. The primary objective of the present study was to determine the feasibility and reliability (intraobserver and interobserver variability) of tissue Doppler and myocardial deformation imaging for evaluating myocardial function in preterm infants undergoing surgical PDA ligation. Additionally, we sought to study the immediate effect of surgical ligation on the left ventricular tissue Doppler and strain measurements in the first 24 hours after surgery. METHODS: Echocardiography was performed in 19 preterm infants before, 1 hour after, and 18 hours after PDA ligation born at 24-29 weeks of gestation. The tissue Doppler velocities of the lateral tricuspid and lateral and septal mitral valve annuli were obtained. The global and regional longitudinal peak systolic strain values were determined using two-dimensional speckle tracking echocardiography. The results of the three measurement points were compared using repeated measures analysis of variance. The intra- and interobserver variability was assessed using the intraclass correlation coefficient and Bland-Altman analysis. RESULTS: The median gestational age was 25.0 weeks (interquartile range 24.9-25.9) and the birth weight was 750 g (interquartile range 600-810). For the global longitudinal strain, the intraobserver intraclass correlation coefficient was 0.92 (95% CI, 0.78-0.97, P < .001), and the interobserver intraclass correlation coefficient was 0.93 (95% CI, 0.66-0.98, P < .001). Bland-Altman analysis showed no significant bias between the two observers, with good agreement. The systolic and diastolic tissue Doppler velocities of the mitral valve decreased significantly immediately after ligation and remained significantly lower than the preoperative levels at 18 hours. Also, the global longitudinal strain values significantly decreased 1 hour after the procedure (global longitudinal strain before -19.7% ± -3.8% vs -11.5% ± -3.5%; P = .001) but had significantly improved 18 hours after the procedure (-15.1% ± -2.9%, P = .01). CONCLUSIONS: The present study has shown the feasibility and reliability of using tissue Doppler and strain imaging in premature infants with a hemodynamically significant PDA. Significant changes in myocardial function were observed immediately after PDA ligation, suggesting important changes in myocardial performance immediately after ductal ligation.

The Use of N-Terminal-Pro-BNP in Preterm Infants.

The use of natriuretic peptides in the neonatal population is emerging. B-type Natriuretic Peptide (BNP) and N-terminal-Pro-BNP (NTpBNP) are used in the adult population to assess myocardial function and volume loading. Their role in prognosis following cardiac surgery has also been identified. In preterm infants NTpBNP is becoming increasingly recognised as a potential screening tool for patent ductus arteriosus (PDA), and a marker for myocardial performance. In addition, NTpBNP may provide prognostic information in preterm infants and term infants with congenital diaphragmatic hernia (CDH). In this paper, the role of NTpBNP in the preterm population will be discussed.

Serum troponin in neonatal intensive care.

Cardiac troponins have a major role in screening and diagnosis of myocardial ischaemia in adults and children. Their introduction has redefined the diagnosis of myocardial infarction in adults and provided valuable prognostic information. In the paediatric population, troponins show a good correlation with the extent of myocardial damage following cardiac surgery and cardiotoxic medication, and can be used as predictors of subsequent cardiac recovery and mortality. This review discusses the current established reference values in term and preterm infants and demonstrates their potential use in neonatology. They may serve as a useful adjunct in the assessment of the magnitude of myocardial injury in respiratory distress syndrome and asphyxia. They may also benefit centres without on-site echocardiography with some evidence showing good correlation with echo-derived markers of myocardial function. The use of troponins in the neonatal unit remains a research tool. More work is needed to explore their prognostic role and monitoring response to treatment following cardioprotective strategies. In preterm infants the effect of inotropes on myocardial function needs further study and troponin may form an integral part of this research.