Cardiac performance in the first year of age among preterm infants fed maternal breast milk

Importance: There is a beneficial association between human breast milk exposure in the neonatal period and cardiac mechanics in adults who were born preterm. It is unknown whether this benefit is apparent in infants in the first year of age. Objective: To test the hypothesis that higher consumption of mother\u27s own milk in preterm infants is associated with enhanced cardiac performance during the first year of age. Design, Setting, and Participants: This cross-sectional study of cardiac and nutritional data at an academic medical center included 80 individuals born preterm and 100 individuals in the control group born full-term. All births were between 2011 and 2013. Two-dimensional echocardiograms were performed at 32 weeks\u27 and 36 weeks\u27 postmenstrual age and at 1 year\u27s corrected age in individuals born preterm and at 1 month and 1 year of age in individuals born full-term. Statistical analysis was performed from January to May 2021. Exposures: Consumption of mother\u27s own milk. Main Outcomes and Measures: Main study outcomes included echocardiography measures of right and left ventricle longitudinal strain (function), left ventricle mass index and right ventricular areas (morphology), and pulmonary vascular resistance (pulmonary hemodynamics) at age 1 year. Results: Of 180 infants included in the study, 97 (54%) were Black infants and 89 (49%) were female infants. Among the 80 infants born in the preterm cohort, 43 (54%) were female infants and 43 (54%) were Black infants. The median gestational age at birth of the preterm infants was 27.0 weeks (interquartile range, 26.0-28.0 weeks) and the median birth weight was 960 g (interquartile range, 800-1138). For each week of exposure to mother\u27s own milk, preterm infants had greater magnitudes of right ventricular strain (eg, right longitudinal strain: β, 0.021; 95% CI, 0.002-0.041; P \u3c .001) and left ventricular strain (eg, left longitudinal strain: β, 0.065; 95% CI, 0.049-0.080; P = .01), larger right ventricle areas (eg, systolic area: β, 0.026; 95% CI, 0.011-0.042; P = .009), larger left ventricle mass index (β, 0.045; 95% CI, 0.024-0.073; P = .003), and decreased pulmonary vascular resistance (eg, pulmonary artery acceleration time: β, 0.041; 95% CI, 0.018-0.063; P \u3c .001) at 1 year\u27s corrected age, even after accounting for gestational age and common neonatal morbidities. Cardiac values approached those seen in controls born full-term with increased mother\u27s own milk exposure. There were no differences in any of the cardiac indices at 32 weeks\u27 postmenstrual age, but with each week of exposure, right ventricle function (eg, right longitudinal strain: β, 0.016; 95% CI, 0.002-0.031; P \u3c .001) was greater and pulmonary pressured (eg, pulmonary artery acceleration time: β, 0.0032; 95% CI, 0.0013-0.0062; P \u3c .001). Conclusions and Relevance: This study found that preterm infants with higher consumption of mother\u27s own milk had enhanced cardiac performance at age 1 year, suggesting that mother\u27s own milk consumption may play a dynamic modulator role on cardiac mechanics in preterm-born infants and help in normalization of the preterm cardiac phenotype

Modified Bluegrass Appliance: A Nonpunitive Therapy for Thumb Sucking in Pediatric Patients—A Case Report with Review of the Literature

Oral habits in form of digit/thumb sucking are common phenomenon and part of childhood behavior. They are normally associated with oral pleasure, hunger, anxiety, and sometimes psychological disturbances. Chronic practice can cause major orthopedic alterations to the skeletal structures of the oral cavity and lower face. Aversive approaches in form of punitive therapy have been moderately effective. Modified bluegrass appliance is nonpunitive therapy to treat sucking habits. It acts as a habit reversal technique and installs positive reinforcement in children. Modified blue grass appliance proved to be very comfortable to patients and encourages neuromuscular stimulations

The role of capital controls in mediating global shocks

To compare the effect of oral glucose given with or without facilitated tucking (FT), versus placebo (water) to facilitate image acquisition during a targeted neonatal echocardiography (TNE).Factorial, double blind, randomized controlled trial.Tertiary neonatal intensive care unit (NICU).Infants born between 26 and 42 weeks of gestation (GA).One of four treatment groups: oral water (placebo), oral glucose (25%), facilitated tucking with oral water or facilitated tucking with oral glucose, during a single, structured TNE. All infants received a soother.Change in Behavioral Indicators of Infant Pain (BIIP) scores.104 preterm infants were randomized (mean ± SD GA: 33.4 ± 3.5 weeks). BIIP scores remained low during the echocardiography scan (median, [IQ range]: 0, [0 to 1]). There were no differences in the level of agitation of infants amongst the treatment groups, with estimated reductions in mean BIIP relative to control of 0.27 (95%CI -0.40 to 0.94) with use of oral glucose and .04 (-0.63 to 0.70) with facilitated tucking. There were also no differences between treatment groups in the quality and duration of the echocardiography scans.In stable infants in the NICU, a TNE can be performed with minimal disruption in a majority of cases, simply by providing a soother. The use of 25% glucose water in this context did not provide further benefit in reducing agitation and improving image acquisition.Clinical Trials.gov: NCT01253889

Relationship between cerebral oxygenation, cardiac output, and blood pressure during transitional period in extremely low gestational age neonates

ObjectiveTo describe the relationship between cerebral oxygenation, cardiac output, arterial blood pressure (BP), and cerebral blood flow velocity in extremely low gestational age neonates (ELGANs) during transition.MethodsThis study comprises secondary analyses from a prospective observational study conducted at a tertiary Neonatal Intensive Care Unit. Recruited ELGANs underwent cerebral saturation (CrSO2) monitoring and serial echocardiography during 72 h from birth. Correlative analyses of CrSO2 and cerebral fractional tissue oxygen extraction (CFTOE) with left (LVO) and right ventricular output (RVO), superior vena cava (SVC) flow, middle cerebral artery blood flow mean velocity (MCA.MV), systolic (SBP), diastolic (DBP), and mean (MBP) BP were conducted.ResultsFifty ELGANs with median (range) gestational age of 25.9 (23.1–27.9) weeks were recruited. Echocardiography was performed sequentially at a median (range) age 5.0 (3.8–6.6), 17.3 (15.4–19.4), 31.0 (27.0–34.1), and 53.7 (49.3–58.3) hours. RVO, LVO, CrSO2, and SBP increased over time but no changes in MBP, DBP, CFTOE, MCA.MV or SVC flow were noted. A weak correlation was identified between CrSO2 and SBP (r2 = 0.11, p = 0.047) and MBP (r2 = 0.12, p = 0.04) at 17.3 (15.4–19.4) hours. No correlation of either CrSO2 or CFTOE with any measures of blood flow was identified.ConclusionThere is a weak correlation between measures of cardiac output, BP, and MCA.MV with both CrSO2 and CFTOE in ELGANs during transition. Whether this finding suggests intact cerebral autoregulation requires prospective evaluation in a cohort of sick ELGANs

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

Relative effectiveness and safety of pharmacotherapeutic agents for patent ductus arteriosus (PDA) in preterm infants: A protocol for a multicentre comparative effectiveness study (CANRxPDA)

Introduction Patent ductus arteriosus (PDA) is the most common cardiovascular problem that develops in preterm infants and evidence regarding the best treatment approach is lacking. Currently available medical options to treat a PDA include indomethacin, ibuprofen or acetaminophen. Wide variation exists in PDA treatment practices across Canada. In view of this large practice variation across Canadian neonatal intensive care units (NICUs), we plan to conduct a comparative effectiveness study of the different pharmacotherapeutic agents used to treat the PDA in preterm infants. Methods and analysis A multicentre prospective observational comparative-effectiveness research study of extremely preterm infants born 29 weeks gestational age with an echocardiography confirmed PDA will be conducted. All participating sites will self-select and adhere to one of the following primary pharmacotherapy protocols for all preterm babies who are deemed to require treatment. Standard dose ibuprofen (10 mg/kg followed by two doses of 5 mg/kg at 24 hours intervals) irrespective of postnatal age (oral/intravenous). Adjustable dose ibuprofen (oral/intravenous) (10 mg/kg followed by two doses of 5 mg/kg at 24 hours intervals if treated within the first 7 days after birth. Higher doses of ibuprofen up to 20 mg/kg followed by two doses of 10 mg/kg at 24 hours intervals if treated after the postnatal age cut-off for lower dose as per the local centre policy). Acetaminophen (oral/intravenous) (15 mg/kg every 6 hours) for 3-7 days. Intravenous indomethacin (0.1-0.3 mg/kg intravenous every 12-24 hours for a total of three doses). Outcomes The primary outcome is failure of primary pharmacotherapy (defined as need for further medical and/or surgical/interventional treatment following an initial course of pharmacotherapy). The secondary outcomes include components of the primary outcome as well as clinical outcomes related to response to treatment or adverse effects of treatment. Sites and sample size The study will be conducted in 22 NICUs across Canada with an anticipated enrollment of 1350 extremely preterm infants over 3 years. Analysis To examine the relative effectiveness of the four treatment strategies, the primary outcome will be compared pairwise between the treatment groups using χ 2 test. Secondary outcomes will be compared pairwise between the treatment groups using χ 2 test, Student\u27s t-test or Wilcoxon rank sum test as appropriate. To further examine differences in the primary and secondary outcomes between the four groups, multiple logistic or linear regression models will be applied for each outcome on the treatment groups, adjusted for potential confounders using generalised estimating equations to account for within-unit-clustering. As a sensitivity analysis, the difference in the primary and secondary outcomes between the treatment groups will also be examined using propensity score method with inverse probability weighting approach. Ethics and dissemination The study has been approved by the IWK Research Ethics Board (#1025627) as well as the respective institutional review boards of the participating centres. © 2021 Author(s). Published by BMJ

Hypotension following Patent Ductus Arteriosus Ligation: The Role of Adrenal Hormones

OBJECTIVE: To test the hypothesis that an impaired adrenal response to stress might play a role in the hypotension that follows patent ductus arteriosus (PDA) ligation. STUDY DESIGN: We performed a multicenter study of infants born at <32 weeks gestation who were about to undergo PDA ligation. Serum adrenal steroids were measured three times: before and after a cosyntropin (1.0 microgram/kg) stimulation test (performed prior to the ligation), and at 10–12 hours after the ligation. A standardized approach for diagnosis and treatment of postoperative hypotension was followed at each site. A modified Inotrope Score (1 x dopamine (μg/kg/min) + 1 x dobutamine) was used to monitor the catecholamine support an infant received. Infants were considered to have catecholamine-resistant hypotension if their highest Inotrope Score was >15. RESULTS: Of 95 infants enrolled, 43 (45%) developed hypotension and 14 (15%) developed catecholamine-resistant hypotension. Low post-operative cortisol levels were not associated with the overall incidence of hypotension following ligation. However, low cortisol levels were associated with the refractoriness of the hypotension to catecholamine treatment. In a multivariate analysis: the odds ratio for developing catecholamine-resistant hypotension was OR=36.6, CI=2.8–476, p=0.006. Low cortisol levels (in infants with catecholamine-resistant hypotension) were not due to adrenal immaturity or impairment; their cortisol precursor concentrations were either low or unchanged and their response to cosyntropin was similar to infants without catecholamine-resistant hypotension. CONCLUSION: Infants with low cortisol concentrations following PDA ligation are likely to develop postoperative catecholamine-resistant hypotension. We speculate that decreased adrenal stimulation, rather than an impaired adrenal response to stimulation, may account for the decreased production

Hyperimmune immunoglobulin for hospitalised patients with COVID-19 (ITAC): a double-blind, placebo-controlled, phase 3, randomised trial

BACKGROUND: Passive immunotherapy using hyperimmune intravenous immunoglobulin (hIVIG) to SARS-CoV-2, derived from recovered donors, is a potential rapidly available, specific therapy for an outbreak infection such as SARS-CoV-2. Findings from randomised clinical trials of hIVIG for the treatment of COVID-19 are limited. METHODS: In this international randomised, double-blind, placebo-controlled trial, hospitalised patients with COVID-19 who had been symptomatic for up to 12 days and did not have acute end-organ failure were randomly assigned (1:1) to receive either hIVIG or an equivalent volume of saline as placebo, in addition to remdesivir, when not contraindicated, and other standard clinical care. Randomisation was stratified by site pharmacy; schedules were prepared using a mass-weighted urn design. Infusions were prepared and masked by trial pharmacists; all other investigators, research staff, and trial participants were masked to group allocation. Follow-up was for 28 days. The primary outcome was measured at day 7 by a seven-category ordinal endpoint that considered pulmonary status and extrapulmonary complications and ranged from no limiting symptoms to death. Deaths and adverse events, including organ failure and serious infections, were used to define composite safety outcomes at days 7 and 28. Prespecified subgroup analyses were carried out for efficacy and safety outcomes by duration of symptoms, the presence of anti-spike neutralising antibodies, and other baseline factors. Analyses were done on a modified intention-to-treat (mITT) population, which included all randomly assigned participants who met eligibility criteria and received all or part of the assigned study product infusion. This study is registered with ClinicalTrials.gov, NCT04546581. FINDINGS: From Oct 8, 2020, to Feb 10, 2021, 593 participants (n=301 hIVIG, n=292 placebo) were enrolled at 63 sites in 11 countries; 579 patients were included in the mITT analysis. Compared with placebo, the hIVIG group did not have significantly greater odds of a more favourable outcome at day 7; the adjusted OR was 1·06 (95% CI 0·77–1·45; p=0·72). Infusions were well tolerated, although infusion reactions were more common in the hIVIG group (18·6% vs 9·5% for placebo; p=0·002). The percentage with the composite safety outcome at day 7 was similar for the hIVIG (24%) and placebo groups (25%; OR 0·98, 95% CI 0·66–1·46; p=0·91). The ORs for the day 7 ordinal outcome did not vary for subgroups considered, but there was evidence of heterogeneity of the treatment effect for the day 7 composite safety outcome: risk was greater for hIVIG compared with placebo for patients who were antibody positive (OR 2·21, 95% CI 1·14–4·29); for patients who were antibody negative, the OR was 0·51 (0·29–0·90; pinteraction=0·001). INTERPRETATION: When administered with standard of care including remdesivir, SARS-CoV-2 hIVIG did not demonstrate efficacy among patients hospitalised with COVID-19 without end-organ failure. The safety of hIVIG might vary by the presence of endogenous neutralising antibodies at entry. FUNDING: US National Institutes of Health

Comprehensive Echocardiographic Evaluation of Cardiac Function and Pulmonary Hemodynamics in the Newly Born during Health and Disease

Very little is known about heart function or pulmonary hemodynamics in newborn infants in either health or disease states. Animal experiments have shown that the immediate period following birth is characterized by an increase in pulmonary blood flow, a decrease in pulmonary vascular resistance and closure of fetal shunts. The specific timing and rate of these events in human neonates are not well documented. The adaptation of an immature heart during this phase of physiological â pulmonary hypertensionâ has also not been studied. Persistent pulmonary hypertension of newborn (PPHN), a frequent outcome of dysregulation of postnatal adaptation, is associated with significant mortality and morbidity, however, the role of cardiac dysfunction is not well known. Clinical appraisal of cardiac performance is difficult in neonates. Two dimensional echocardiography, the only routinely feasible investigation, has undergone significant technological advancements, making it suitable to study human neonatal cardiac physiology. In the studies reported herein, I demonstrated the feasibility and utility of employing quantitative echocardiography measures for studying cardiopulmonary physiology during the immediate postnatal period, in both health and diseased states. I prospectively established a comprehensive set of normative values for various echocardiographic indices of biventricular cardiac function and pulmonary hemodynamics during the first two days of life and described their relative measurement reliability. Subsequently, for the first time, I provided time-sensitive, quantitative, physiological circulatory data regarding immediate postnatal transition in humans, starting fromPh.D

Effect of Phenobarbitone on Amplitude-Integrated Electroencephalography in Neonates with Hypoxic-Ischemic Encephalopathy during Hypothermia

Background: Phenobarbitone induces suppression of cerebral electrical activity on amplitude-integrated electroencephalography (aEEG) in neonates with hypoxic-ischemic encephalopathy (HIE); however, its effect during therapeutic hypothermia (TH) has not been well characterized. Objective: To evaluate the effect of phenobarbitone on aEEG in neonates with HIE undergoing TH. Methods: Thirty-five neonates born at ≥350 weeks gestational age (GA), who received phenobarbitone as first-line antiepileptic drug during TH for ≥ Sarnat stage II HIE with aEEG recordings were retrospectively studied. Background pattern, upper and lower margin voltages were characterized for a 30-min period before and 30–60 min after phenobarbitone administration. Primary outcome was presence of severely abnormal aEEG pattern after phenobarbitone administration. Results: Mean (±SD) GA and median birth weight were 38.2 ± 1.9 weeks and 3.1 (2.5–3.9) kg, respectively. Phenobarbitone (10–20 mg/kg), administered at median age 16.8 h, was associated with background pattern worsening in 19/29 (65.5%) cases. Severe background patterns were more prevalent in post- versus pre-phenobarbitone tracings (21/29 [72%] vs. 11/29 [38%]; p = 0.01). Presence of severe pattern versus either continuous normal voltage or discontinuous normal voltage pattern post-phenobarbitone, (20/25 [80%] vs. 3/8 [38%]; p = 0.036) was associated with death or moderate-to-severe injury on MRI brain. Median time to trace recovery, when measurable, was 4 h (45 min–72 h). Conclusions: Phenobarbitone induces significant suppression on aEEG in infants with HIE undergoing TH. Development of severe aEEG background patterns after phenobarbitone may unmask a population at greater risk of abnormal outcome