Reassessing the role of milrinone in the treatment of heart failure and pulmonary hypertension in neonates and children: a systematic review and meta-analysis.

To evaluate milrinone's impact on pediatric cardiac function, focusing on its specific role as an inotrope and lusitrope, while considering its systemic and pulmonary vasodilatory effects. Search of PubMed, EMBASE, and the Cochrane Library up to August 2023. We included all studies that evaluated milrinone in children under 18 years old in neonatal, pediatric, or cardiac intensive care units. We excluded case reports, studies that did not provide tabular information on milrinone's outcomes, and studies focused on non-intensive care populations. We extracted data on the research design, objectives, study sample, and results of each study, including the impact of milrinone and any associated factors. We screened a total of 9423 abstracts and 41 studies were ultimately included. Milrinone significantly improved left ventricular ejection fraction (WMD 3.41 [95% CI 0.61 - 6.21]), left ventricle shortening fraction (WMD 4.25 [95% CI 3.43 - 5.08]), cardiac index (WMD 0.50 [95% CI 0.32 to 0.68]), left ventricle output (WMD 55.81 [95% CI 4.91 to 106.72]), serum lactate (WMD -0.59 [95% CI -1.15 to -0.02]), and stroke volume index (WMD 2.95 [95% CI 0.09 - 5.82]). However, milrinone was not associated with improvements in ventricular myocardial performance index (WMD -0.01 [95% CI -0.06 to 0.04]) and ventricular longitudinal strain (WMD -2.14 [95% CI -4.56 to 0.28]). Furthermore, milrinone was not associated with isovolumetric relaxation time reduction (WMD -8.87 [95% CI -21.40 to 3.66]). CONCLUSION: Our meta-analysis suggests potential clinical benefits of milrinone by improving cardiac function, likely driven by its systemic vasodilatory effects. However, questions arise about its inotropic influence and the presence of a lusitropic effect. Moreover, milrinone's pulmonary vasodilatory effect appears relatively weaker compared to its systemic actions. Further research is needed to elucidate milrinone's precise mechanisms and refine its clinical applications in pediatric practice. WHAT IS KNOWN: • Milrinone is a phosphodiesterase III inhibitor that has been used to treat a variety of pediatric and neonatal conditions. • Milrinone is believed to exert its therapeutic effects by enhancing cardiac contractility and promoting vascular relaxation. WHAT IS NEW: • Milrinone may not have a significant inotropic effect. • Milrinone's pulmonary vasodilatory effect is less robust than its systemic vasodilatory effect.

Association between Serum Lactate and Morbidity and Mortality in Neonates: A Systematic Review and Meta-Analysis.

OBJECTIVE: Lactate is a marker of hypoperfusion in critically ill patients. Whether lactate is useful for identifying and stratifying neonates with a higher risk of adverse outcomes remains unknown. This study aimed to investigate the association between lactate and morbidity and mortality in neonates. METHODS: A meta-analysis was performed to determine the association between blood lactate levels and outcomes in neonates. Ovid MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov were searched from inception to 1 May 2021. A total of 49 observational studies and 14 data accuracy test studies were included. The risk of bias was assessed using the Newcastle-Ottawa Scale for observational studies and the QUADAS-2 tool for data accuracy test studies. The primary outcome was mortality, while the secondary outcomes included acute kidney injury, necessity for renal replacement therapy, neurological outcomes, respiratory morbidities, hemodynamic instability, and retinopathy of prematurity. RESULTS: Of the 3184 articles screened, 63 studies fulfilled all eligibility criteria, comprising 46,069 neonates. Higher lactate levels are associated with mortality (standard mean difference, -1.09 [95% CI, -1.46 to -0.73]). Using the estimated sensitivity (0.769) and specificity (0.791) and assuming a prevalence of 15% for adverse outcomes (median of prevalence among studies) in a hypothetical cohort of 10,000 neonates, assessing the lactate level alone would miss 346 (3.46%) cases (false negative) and wrongly diagnose 1776 (17.76%) cases (false positive). CONCLUSIONS: Higher lactate levels are associated with a greater risk of mortality and morbidities in neonates. However, our results do not support the use of lactate as a screening test to identify adverse outcomes in newborns. Research efforts should focus on analyzing serial lactate measurements, rather than a single measurement.

Factors associated with cholestasis in newborns with gastroschisis.

OBJECTIVE: To describe the incidence and to analyze risk factors associated with cholestasis in neonates with gastroschisis. METHODS: This is a retrospective cohort study in a tertiary single center analyzing 181 newborns with gastroschisis between 2009 and 2020. The following risk factors associated with cholestasis were analyzed: gestational age, birth weight, type of gastroschisis, silo closure or immediate closure, days of parenteral nutrition, type of lipid emulsion, days of fasting, days to reach a full diet, days with central venous catheter, presence of infections, and outcomes. RESULTS: Among the 176 patients evaluated, 41 (23.3%) evolved with cholestasis. In the univariate analysis, low birth weight (p=0.023), prematurity (p<0.001), lipid emulsion with medium-chain triglycerides and long-chain triglycerides (p=0.001) and death (p<0.001) were associated with cholestasis. In the multivariate analysis, patients who received lipid emulsion with fish oil instead of medium chain triglycerides/long chain triglycerides (MCT/LCT) emulsion had a lower risk of cholestasis. CONCLUSIONS: Our study shows that lipid emulsion with fish oil is associated with a lower risk of cholestasis in neonates with gastroschisis. However, this is a retrospective study and a prospective study should be performed to confirm the results.

Identifying two distinct subphenotypes of patent ductus arteriosus in preterm infants using machine learning.

To use unsupervised machine learning to identify potential subphenotypes of preterm infants with patent ductus arteriosus (PDA). The study was conducted retrospectively at a neonatal intensive care unit in Brazil. Patients with a gestational age < 28 weeks who had undergone at least one echocardiogram within the first two weeks of life and had PDA size > 1.5 or LA/AO ratio > 1.5 were included. Agglomerative hierarchical clustering on principal components was used to divide the data into different clusters based on common characteristics. Two distinct subphenotypes of preterm infants with hemodynamically significant PDA were identified: "inflamed," characterized by high leukocyte, neutrophil, and neutrophil-to-lymphocyte ratio, and "respiratory acidosis," characterized by low pH and high pCO2 levels.    Conclusions: This study suggests that there may be two distinct subphenotypes of preterm infants with hemodynamically significant PDA: "inflamed" and "respiratory acidosis." By dividing the population into different subgroups based on common characteristics, it is possible to get a more nuanced understanding of the effectiveness of PDA interventions. What is Known: • Treatment of PDA in preterm infants has been controversial. • Stratification of preterm infants with PDA into subgroups is important in order to determine the best treatment. What is New: • Unsupervised machine learning was used to identify two subphenotypes of preterm infants with hemodynamically significant PDA. • The 'inflamed' cluster was characterized by higher values of leukocyte, neutrophil, and neutrophil-to-lymphocyte ratio. The 'respiratory acidosis' cluster was characterized by lower pH values and higher pCO2 values.

Complete blood count and C-reactive protein to predict positive blood culture among neonates using machine learning algorithms.

PURPOSE: The authors aimed to develop a Machine-Learning (ML) algorithm that can predict positive blood culture in the neonatal intensive care unit, using complete blood count and C-reactive protein values. METHODS: The study was based on patients' electronic health records at a tertiary neonatal intensive care unit in São Paulo, Brazil. All blood cultures that had paired complete blood count and C-reactive protein measurements taken at the same time were included. To evaluate the machine learning model's performance, the authors used accuracy, Area Under the Receiver Operating Characteristics (AUROC), recall, precision, and F1-score. RESULTS: The dataset included 1181 blood cultures with paired complete blood count plus c-reactive protein and 1911 blood cultures with paired complete blood count only. The f1-score ranged from 0.14 to 0.43, recall ranged from 0.08 to 0.59, precision ranged from 0.29 to 1.00, and accuracy ranged from 0.688 to 0.864. CONCLUSION: Complete blood count parameters and C-reactive protein levels cannot be used in ML models to predict bacteremia in newborns.

Complete blood count and C-reactive protein to predict positive blood culture among neonates using machine learning algorithms

Abstract Purpose: The authors aimed to develop a Machine-Learning (ML) algorithm that can predict positive blood culture in the neonatal intensive care unit, using complete blood count and C-reactive protein values. Methods: The study was based on patients' electronic health records at a tertiary neonatal intensive care unit in São Paulo, Brazil. All blood cultures that had paired complete blood count and C-reactive protein measurements taken at the same time were included. To evaluate the machine learning model's performance, the authors used accuracy, Area Under the Receiver Operating Characteristics (AUROC), recall, precision, and F1-score. Results: The dataset included 1181 blood cultures with paired complete blood count plus c-reactive protein and 1911 blood cultures with paired complete blood count only. The f1-score ranged from 0.14 to 0.43, recall ranged from 0.08 to 0.59, precision ranged from 0.29 to 1.00, and accuracy ranged from 0.688 to 0.864. Conclusion: Complete blood count parameters and C-reactive protein levels cannot be used in ML models to predict bacteremia in newborns.

Factors associated with cholestasis in newborns with gastroschisis / Fatores associados à colestase em recém-nascidos com gastrosquise

ABSTRACT Objective: To describe the incidence and to analyze risk factors associated with cholestasis in neonates with gastroschisis. Methods: This is a retrospective cohort study in a tertiary single center analyzing 181 newborns with gastroschisis between 2009 and 2020. The following risk factors associated with cholestasis were analyzed: gestational age, birth weight, type of gastroschisis, silo closure or immediate closure, days of parenteral nutrition, type of lipid emulsion, days of fasting, days to reach a full diet, days with central venous catheter, presence of infections, and outcomes. Results: Among the 176 patients evaluated, 41 (23.3%) evolved with cholestasis. In the univariate analysis, low birth weight (p=0.023), prematurity (p<0.001), lipid emulsion with medium-chain triglycerides and long-chain triglycerides (p=0.001) and death (p<0.001) were associated with cholestasis. In the multivariate analysis, patients who received lipid emulsion with fish oil instead of medium chain triglycerides/long chain triglycerides (MCT/LCT) emulsion had a lower risk of cholestasis. Conclusions: Our study shows that lipid emulsion with fish oil is associated with a lower risk of cholestasis in neonates with gastroschisis. However, this is a retrospective study and a prospective study should be performed to confirm the results.

RESUMO Objetivo: Analisar a incidência e os fatores de risco associados à colestase em recém-nascidos com gastrosquise. Métodos: Estudo de coorte retrospectivo em um único centro terciário, que analisou 181 recém-nascidos com gastrosquise entre 2009 e 2020. Foram examinados os seguintes fatores de risco associados à colestase: idade gestacional, peso ao nascer, tipo de gastrosquise, fechamento com silo ou fechamento imediato, dias de uso nutrição parenteral, tipo de emulsão lipídica, dias de jejum, dias para atingir a dieta completa, dias com cateter venoso central, presença de infecções e desfechos. Resultados: Dos 176 pacientes avaliados, 41 (23,3%) evoluíram com colestase. Baixo peso ao nascer (p=0,023), prematuridade (p<0,001), emulsão lipídica com triglicerídeos de cadeia média e triglicerídeos de cadeia longa (p=0,001) e óbito (p<0,001) foram associados à colestase. Na análise multivariada, os pacientes que receberam emulsão lipídica com óleo de peixe em vez da emulsão diária de triglicérides de cadeia média/triglicérides de cadeia longa (MCT/LCT) apresentaram menor risco de colestase. Conclusões: Nosso estudo mostra que a emulsão lipídica com óleo de peixe está associada a menor risco de colestase em neonatos com gastrosquise, porém este é um estudo retrospectivo, e um estudo prospectivo deve ser realizado para confirmar os resultados.

Gastroschisis and late-onset neonatal sepsis in a tertiary referral center in Southeastern Brazil

Abstract Objectives: To analyze late-onset sepsis and to describe the etiological agents in newborns with gastroschisis. Methods: A retrospective cohort, including newborns with gastroschisis whose admissions occurred in the period between January 2012 to December 2018 in a tertiary referral center. Maternal and newborn characteristics, surgical procedures and evolution in hospitalization were verified. A bivariate analysis was performed with patients with proven late-onset neonatal sepsis and according to the simple or complex gastroschisis category, the prevalent microorganisms in positive cultures were identified, statistical tests were carried out and the significance level adopted was p < 0,05. Results are presented in proportions, averages and standard deviation or medians. The level of significance adopted was p < 0.05. Results: 101 newborns were analyzed, 45 (44.5%) were confirmed late-onset sepsis. The median birth weight was 2285+498 grams, and the gestational age was 35.9 +1.74weeks. The incidence of complex gastroschisis was 17.8%, the hospitalization time was 48.2+29.67 days and mortality was 9.9%. The newborns were divided into 2 groups: Group 1: late-onset sepsis (44.6%), and Group 2: no late-onset sepsis. The presence of complex gastroschisis was a factor associated with infection (p < 0.009). Fasting time (p < 0.001), parenteral nutrition time (p < 0.001), time to achieve full diet (p < 0.001), and hospitalization stay (p < 0.001) were higher in group 2. Gram-positive were the most frequent (51.1%), followed by Gram-negative (20%), and fungi (4.4%). Conclusions: Newborns with gastroschisis have a higher risk of evolving with late-onset sepsis, despite this study did not calculate the risk of sepsis statistically, and the main germs detected by cultures were gram-positive bacteria, specifically Staphylococcus epidermidis.

Gastroschisis and late-onset neonatal sepsis in a tertiary referral center in Southeastern Brazil.

OBJECTIVES: To analyze late-onset sepsis and to describe the etiological agents in newborns with gastroschisis. METHODS: A retrospective cohort, including newborns with gastroschisis whose admissions occurred in the period between January 2012 to December 2018 in a tertiary referral center. Maternal and newborn characteristics, surgical procedures and evolution in hospitalization were verified. A bivariate analysis was performed with patients with proven late-onset neonatal sepsis and according to the simple or complex gastroschisis category, the prevalent microorganisms in positive cultures were identified, statistical tests were carried out and the significance level adopted was p < 0,05. Results are presented in proportions, averages and standard deviation or medians. The level of significance adopted was p < 0.05. RESULTS: 101 newborns were analyzed, 45 (44.5%) were confirmed late-onset sepsis. The median birth weight was 2285+498 grams, and the gestational age was 35.9 +1.74weeks. The incidence of complex gastroschisis was 17.8%, the hospitalization time was 48.2+29.67 days and mortality was 9.9%. The newborns were divided into 2 groups: Group 1: late-onset sepsis (44.6%), and Group 2: no late-onset sepsis. The presence of complex gastroschisis was a factor associated with infection (p < 0.009). Fasting time (p < 0.001), parenteral nutrition time (p < 0.001), time to achieve full diet (p < 0.001), and hospitalization stay (p < 0.001) were higher in group 2. Gram-positive were the most frequent (51.1%), followed by Gram-negative (20%), and fungi (4.4%). CONCLUSIONS: Newborns with gastroschisis have a higher risk of evolving with late-onset sepsis, despite this study did not calculate the risk of sepsis statistically, and the main germs detected by cultures were gram-positive bacteria, specifically Staphylococcus epidermidis.

Association between fluid overload and mortality in newborns: a systematic review and meta-analysis.

Fluid overload (FO) is associated with higher rates of mortality and morbidity in pediatric and adult populations. The aim of this systematic review and meta-analysis was to investigate the association between FO and mortality in critically ill neonates. Systematic search of Ovid MEDLINE, EMBASE, Cochrane Library, trial registries, and gray literature from inception to January 2021. We included all studies that examined neonates admitted to neonatal intensive care units and described FO and outcomes of interest. We identified 17 observational studies with a total of 4772 critically ill neonates who met the inclusion criteria. FO was associated with higher mortality (OR, 4.95 [95% CI, 2.26-10.87]), and survivors had a lower percentage of FO compared with nonsurvivors (WMD, - 4.33 [95% CI, - 8.34 to - 0.32]). Neonates who did not develop acute kidney injury (AKI) had lower FO compared with AKI patients (WMD, - 2.29 [95% CI, - 4.47 to - 0.10]). Neonates who did not require mechanical ventilation on postnatal day 7 had lower fluid balance (WMD, - 1.54 [95% CI, - 2.21 to - 0.88]). FO is associated with higher mortality, AKI, and need for mechanical ventilation in critically ill neonates in the intensive care unit. Strict control of fluid balance to prevent FO is essential. A higher resolution version of the Graphical abstract is available as Supplementary information.

Identifying clinical phenotypes in extremely low birth weight infants-an unsupervised machine learning approach.

There is increasing evidence that patient heterogeneity significantly hinders advancement in clinical trials and individualized care. This study aimed to identify distinct phenotypes in extremely low birth weight infants. We performed an agglomerative hierarchical clustering on principal components. Cluster validation was performed by cluster stability assessment with bootstrapping method. A total of 215 newborns (median gestational age 27 (26-29) weeks) were included in the final analysis. Six clusters with different clinical and laboratory characteristics were identified: the "Mature" (Cluster 1; n = 60, 27.9%), the mechanically ventilated with "adequate ventilation" (Cluster 2; n = 40, 18.6%), the mechanically ventilated with "poor ventilation" (Cluster 3; n = 39, 18.1%), the "extremely immature" (Cluster 4; n = 39, 18.1%%), the neonates requiring "Intensive Resuscitation" in the delivery room (Cluster 5; n = 20, 9.3%), and the "Early septic" group (Cluster 6; n = 17, 7.9%). In-hospital mortality rates were 11.7%, 25%, 56.4%, 61.5%, 45%, and 52.9%, while severe intraventricular hemorrhage rates were 1.7%, 5.3%, 29.7%, 47.2%, 44.4%, and 28.6% in clusters 1, 2, 3, 4, 5, and 6, respectively (p < 0.001).Conclusion: Our cluster analysis in extremely preterm infants was able to characterize six distinct phenotypes. Future research should explore how better phenotypic characterization of neonates might improve care and prognosis. What is Known: • Patient heterogeneity is becoming more acknowledged as a cause of clinical trial failure. • Machine learning algorithms can find patterns within a heterogeneous group. What is New: • We identified six different phenotypes of extremely preterm infants who exhibited distinct clinical and laboratorial characteristics.

Early fluid overload is associated with mortality and prolonged mechanical ventilation in extremely low birth weight infants.

Recent studies revealed that fluid overload is associated with higher mortality in critically ill children and adults. This study aimed to evaluate the association between fluid overload in the first 3 days of life and mortality in extremely low birth weight infants. This single-center retrospective cohort study included two hundred nineteen newborns with birth weight less than 1000 g who were admitted to the neonatal intensive care between January 2012 and December 2017. Overall mortality was 32.4%, the median gestational age was 27.3 (26.1-29.4) weeks, and birth weight was 770 (610-900) grams. In the group with severe fluid overload, we found a higher rate of deaths (72.2%); mean airway pressure was significantly higher and with longer invasive mechanical ventilation necessity.Conclusion: Early fluid overload in extremely low birth weight infants is associated with higher mortality rate, higher mean airway pressure in invasive mechanically ventilated patients, and longer mechanical ventilation duration in the first 7 days of life. What is Known: • Fluid overload is associated with a higher mortality rate and prolonged mechanical ventilation in children and adults. What is New: • Fluid overload in the first 72 h of life in an extremely premature infant is associated with higher mortality rate, higher mean airway pressure in invasive mechanically ventilated patients, and longer mechanical ventilation duration the first 7 days of life.

A haploid genetic screen identifies the G1/S regulatory machinery as a determinant of Wee1 inhibitor sensitivity.

The Wee1 cell cycle checkpoint kinase prevents premature mitotic entry by inhibiting cyclin-dependent kinases. Chemical inhibitors of Wee1 are currently being tested clinically as targeted anticancer drugs. Wee1 inhibition is thought to be preferentially cytotoxic in p53-defective cancer cells. However, TP53 mutant cancers do not respond consistently to Wee1 inhibitor treatment, indicating the existence of genetic determinants of Wee1 inhibitor sensitivity other than TP53 status. To optimally facilitate patient selection for Wee1 inhibition and uncover potential resistance mechanisms, identification of these currently unknown genes is necessary. The aim of this study was therefore to identify gene mutations that determine Wee1 inhibitor sensitivity. We performed a genome-wide unbiased functional genetic screen in TP53 mutant near-haploid KBM-7 cells using gene-trap insertional mutagenesis. Insertion site mapping of cells that survived long-term Wee1 inhibition revealed enrichment of G1/S regulatory genes, including SKP2, CUL1, and CDK2. Stable depletion of SKP2, CUL1, or CDK2 or chemical Cdk2 inhibition rescued the γ-H2AX induction and abrogation of G2 phase as induced by Wee1 inhibition in breast and ovarian cancer cell lines. Remarkably, live cell imaging showed that depletion of SKP2, CUL1, or CDK2 did not rescue the Wee1 inhibition-induced karyokinesis and cytokinesis defects. These data indicate that the activity of the DNA replication machinery, beyond TP53 mutation status, determines Wee1 inhibitor sensitivity, and could serve as a selection criterion for Wee1-inhibitor eligible patients. Conversely, loss of the identified S-phase genes could serve as a mechanism of acquired resistance, which goes along with development of severe genomic instability.