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Congenital diaphragmatic hernia (CDH) survivors are at risk of developing significant chronic health conditions and disabilities. The main purpose of this study was to compare the outcomes of CDH infants at 2 years of age (2y) according to whether the infants had undergone fetoscopic tracheal occlusion (FETO) during the prenatal period and characterize the relationship between morbidity at 2y and perinatal characteristics. Retrospective cohort single center study. Eleven years of clinical follow-up data (from 2006 to 2017) were collected. Prenatal and neonatal factors as well as growth, respiratory, and neurological evaluations at 2y were analyzed. One hundred and fourteen CDH survivors were evaluated. Failure to thrive (FTT) was present in 24.6% of patients, gastroesophageal reflux disease (GERD) in 22.8%, 28.9% developed respiratory problems, and 22% had neurodevelopment disabilities. Prematurity and birth weight < 2500 g were related to FTT and respiratory morbidity. Time to reach full enteral nutrition and prenatal severity markers seemed to influence all outcomes, but FETO therapy itself only had an effect on respiratory morbidity. Some variables related to postnatal severity (ECMO, patch closure, days on mechanic ventilation, and vasodilator treatment) were associated with almost all outcomes. Conclusion: CDH patients have specific morbidities at 2y, most of them related to lung hypoplasia severity. Only respiratory problems were related to FETO therapy itself. The implementation of a specific multidisciplinary follow-up program for CDH patients is essential to provide them the best standard of care, but, more severe patients, regardless of whether they received prenatal therapy, need a more intensive follow-up. What is Known: ⢠Antenatal fetoscopic endoluminal tracheal occlusion (FETO) increases survival in more severe congenital diaphragmatic hernia patients. ⢠Congenital diaphragmatic hernia survivors are at risk of developing significant chronic health conditions and disabilities. Very limited data are available about the follow-up in patients with congenital diaphragmatic hernia and FETO therapy. What is New: ⢠CDH patients have specific morbidities at 2 years of age, most of them related to lung hypoplasia severity. ⢠FETO patients present more respiratory problems at 2 years of age but they don't have an increased incidence of other morbidities. More severe patients, regardless of whether they received prenatal therapy, need a more intensive follow-up.
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Obstrução das Vias Respiratórias , Hérnias Diafragmáticas Congênitas , Lactente , Recém-Nascido , Humanos , Feminino , Gravidez , Hérnias Diafragmáticas Congênitas/complicações , Hérnias Diafragmáticas Congênitas/cirurgia , Estudos Retrospectivos , Seguimentos , Fetoscopia , Recém-Nascido Prematuro , TraqueiaRESUMO
AIM: There are two types of intestinal volvulus: midgut (MGV) and segmental (SV). Patients with different types of intestinal volvulus are often included in the same case series, which may affect the perception of how severe "intestinal volvuli" are. We aimed to compare both types of intestinal volvulus. METHODS: This is a retrospective observational study including all patients with MGV and SV up to 28 days of life admitted to a tertiary hospital in Spain over a 20-year-period (1999-2019). A comparison between groups and a logistic regression model for mortality were done. RESULTS: We identified 32 patients: 23 MGV and 9 SV. Malrotation was exclusive of MGV. Prenatal diagnosis, cystic fibrosis, and intestinal resection were significantly more frequent in SV. Surgery was performed at a significantly lower age in SV. The mortality observed in acute MGV with intestinal compromise (41.7%) is four times higher than the mortality of SV (11.1%). The overall mortality of all MGV patients (21.7%) is almost twice that of SV. Mortality was best predicted by the presence of hemodynamic instability (OR 27.5 95% CI 2.50-302.17; p = 0.007). CONCLUSION: SV and MGV have a different clinical presentation. Hemodynamic instability is the major risk factor for death.
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Volvo Intestinal , Feminino , Humanos , Recém-Nascido , Volvo Intestinal/diagnóstico , Volvo Intestinal/cirurgia , Intestinos , Gravidez , Diagnóstico Pré-Natal , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: There is evidence that delivery room resuscitation of very preterm infants often deviates from internationally recommended guidelines. There were no published data in Spain regarding the quality of neonatal resuscitation. Therefore, we decided to evaluate resuscitation team adherence to neonatal resuscitation guidelines after birth in very preterm infants. METHODS: We conducted an observational study. We video recorded resuscitations of preterm infants < 32 weeks' gestational age and evaluated every step during resuscitation according to a score-sheet specifically designed for this purpose, following Carbine's method, where higher scores indicated that more intense resuscitation maneuvers were required. We divided the score achieved by the total possible points per patient to obtain the percentage of adherence to the algorithm. We also compared resuscitations performed by staff neonatologists to those performed by pediatricians on-call. We compared percentages of adherence to the algorithm with the Chi-square test for large groups and Fisher's exact test for smaller groups. We compared assigned Apgar scores with those given after analyzing the recordings and described them by their median and interquartile range. We measured the interrater agreement between Apgar scores with Cohen's kappa coefficient. Linear and logarithmic regressions were drawn to characterize the pattern of algorithm adherence. Statistical analysis was performed using SPSS V.20. A p-value < 0.05 was considered significant. Our Hospital Ethics Committee approved this project, and we obtained parental written consent beforehand. RESULTS: Sixteen percent of our resuscitations followed the algorithm. The number of mistakes per resuscitation was low. Global adherence to the algorithm was 80.9%. Ventilation and surfactant administration were performed best, whereas preparation and initial steps were done with worse adherence to the algorithm. Intubation required, on average, 2.2 attempts; success on the first attempt happened in 33.3% of cases. Only 12.5% of intubations were achieved within the allotted 30 s. Many errors were attributable to timing. Resuscitations led by pediatricians on-call were performed as correctly as those by staff neonatologists. CONCLUSIONS: Resuscitation often deviates from the internationally recognized algorithm. Perfectly performed resuscitations are infrequent, although global adherence to the algorithm is high. Neonatologists and pediatricians need intubation training.
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Algoritmos , Fidelidade a Diretrizes , Recém-Nascido Prematuro , Ressuscitação/métodos , Ressuscitação/normas , Centros de Atenção Terciária/normas , Humanos , Recém-Nascido , Guias de Prática Clínica como Assunto , Espanha , Gravação em VídeoRESUMO
OBJECTIVE: To determine if very preterm (VPT) babies are capable of maintaining glucose levels within normal ranges at or near term postmenstrual age. STUDY DESIGN: Glucose levels were intermittently or continuously monitored during 48 hours in a cohort of 60 VPT infants near hospital discharge. Hypoglycemic (≤45 mg/dL, 2.5 mmol/L) and hyperglycemic (≥140 mg/dL or 7.8 mmol/L, severe if ≥180 mg/dL or 10 mmol/L) episodes were considered relevant if they lasted longer than 30 minutes. Feeding regimes followed current practice. RESULTS: With intermittent capillary, 2 hypoglycemic values and another 3 that were abnormally high were detected. With continuous monitoring, 6 babies (10.0%) had isolated hypoglycemia ≤45 mg/dL (2.5 mmol/L) (3 of them reaching 40 mg/dL, 2.2 mmol/L), 14 (23.3%) had isolated hyperglycemia, and 8 (13.3%) had episodes of both. The mean duration of hypoglycemia per patient was 2.8 ± 2.9 hours and 4.68 ± 4.35 hours in the case of hyperglycemia, with 12 infants becoming severely hyperglycemic. Of the 12 severely hyperglycemic patients, 5 also developed severe hypoglycemia. No specific characteristics identified the hypoglycemic babies. A history of intrauterine growth restriction (P = .037) and female sex (P = .063) seemed to increase the risk of severe hyperglycemia. CONCLUSIONS: VPT infants continue to have abnormal glucose values, especially hyperglycemia, by the time of hospital discharge. No specific factors identify babies at higher risk for hypoglycemia, and intrauterine growth restriction and female sex seemed to predispose to hyperglycemia.
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Glicemia/análise , Homeostase/fisiologia , Recém-Nascido Prematuro/fisiologia , Comorbidade , Nutrição Enteral , Feminino , Retardo do Crescimento Fetal/epidemiologia , Retardo do Crescimento Fetal/fisiopatologia , Humanos , Hiperglicemia/epidemiologia , Hipoglicemia/epidemiologia , Masculino , Fatores de RiscoRESUMO
INTRODUCTION: Our aim was to determine which foetal or neonatal growth curves discriminate the probability of dying of newborns with low birth weight for their gestational age (small for gestational age, SGA) and sex (weight < 10th percentile) and to establish the curves that are presumably most useful for monitoring growth through age 10 years. MATERIAL AND METHODS: The analysis included every neonate (15 122) managed in our hospital (2013-2022) and all neonates born preterm before 32 weeks (6913) registered in the SEN1500 database (2019-2022). We considered most useful those curves with the highest likelihood ratio (LR) for dying with or without a history of SGA in each subgroup of gestational ages. Theoretically, the optimal curves for monitoring growth would be those with a higher R2 in the quantile regression formulas for the 50th percentile. RESULTS: The growth curves exhibiting the strongest association between SGA and hospital mortality are the Intergrowth fetal curves and the Fenton neonatal curves in infants born preterm before 32 weeks. However, the optimal curves for premature babies and neonates overall were those of Olsen and Intergrowth. The most useful curves to monitor anthropometric values alone until age 10 years of age are the longitudinal Intergrowth curves followed by the WHO standards, but if a single reference is desired from birth through age 10 years, the best option is the Fenton curves followed by the WHO standards. CONCLUSIONS: The Intergrowth reference provides the most discriminating foetal growth curves. In neonatal clinical practice, the optimal references are the Fenton followed by the WHO charts.
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Desenvolvimento Fetal , Gráficos de Crescimento , Recém-Nascido Pequeno para a Idade Gestacional , Humanos , Recém-Nascido , Feminino , Masculino , Desenvolvimento Fetal/fisiologia , Idade Gestacional , Recém-Nascido Prematuro/crescimento & desenvolvimento , Lactente , Criança , Mortalidade Hospitalar , Recém-Nascido de Baixo PesoRESUMO
A complete, objective and systematic documentation of delivery room resuscitation is important for research, for quality improvement, for teaching and as a reference for postresuscitation care. However, documentation during neonatal resuscitation is usually paper-based, retrospective, inaccurate and unreliable. In this narrative review, we discuss the strengths and pitfalls of current documentation methods in neonatal resuscitation, as well as the challenges of introducing new or emerging technologies in this field. In particular, we discuss innovations in electronic and automated medical records, video recording and Smartphones and Tablet Apps. Given the lack of a consensus standard, we finally propose a list of items that should be part of any neonatal resuscitation documentation method.
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Prontuários Médicos , Ressuscitação , Estudos Retrospectivos , Melhoria de Qualidade , DocumentaçãoRESUMO
BACKGROUND: Birth before term is a stressful experience for parents because of the unexpected delivery or admission to the neonatal intensive care unit. OBJECTIVE: This research aimed to evaluate the impact of the early PT intervention on preterm infants' parents' experiences, and also to obtain knowledge about parents' experiences and perceived difficulties during preterm infants' care. METHODS: This qualitative study is based on the methods of phenomenology. In the first phase, open interviews were developed to allow researchers to immerse themselves in the context of the study and refine the questions for the semi-structured interviews. Data collected from the semi-structured interviews were analyzed through content analysis. RESULTS: The results were summarized around three themes: 1) parental competence; 2) difficulties during preterm infants' care; and 3) coping strategies. Each theme was divided into two sub-themes. CONCLUSION: Mothers and fathers of preterm infants experienced difficulties when caring for their babies. Parents that received the early physiotherapy intervention felt empowered to take care of their babies and to enhance infants' development. These parents were more capable of developing coping strategies after the intervention. Parents that did not receive the early physiotherapy intervention expressed difficulties when caring for their preterm babies.
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Recém-Nascido Prematuro , Pais , Adaptação Psicológica , Feminino , Humanos , Lactente , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Modalidades de Fisioterapia , Pesquisa QualitativaRESUMO
OBJECTIVE: To evaluate trends in respiratory care practices and bronchopulmonary dysplasia (BPD) among very preterm infants born in Spain between 2010 and 2019. STUDY DESIGN: This was a retrospective cohort study of data obtained from a national population-based database (SEN1500 network). Changes in respiratory care and BPD-free survival of infants with gestational age (GA) of 230-316 weeks and <1500 g were assessed over two 5-year periods. Temporal trends were examined by joinpoint and Poisson regression models and expressed as the annual per cent change and adjusted relative risk (RR) for the change per year. RESULTS: A total of 17 952 infants were included. In the second period, infants were less frequently intubated in the delivery room and during neonatal intensive care unit stay. This corresponded with an increase in use of non-invasive ventilation techniques. There were no significant differences between the periods in BPD-free survival or survival without moderate-to-severe BPD. After adjusting for covariates, the RR for the change per year was significant for the following variables: never intubated (RR 1.03, 95% CI 1.02 to 1.04); intubation in the delivery room (RR 0.98, 95% CI 0.97 to 0.99); use of nasal intermittent positive pressure ventilation (RR 1.08, 95% CI 1.05 to 1.11); and BPD-free survival (only in the group with the lowest GA; RR 0.98, 95% CI 0.97 to 0.99). CONCLUSION: Our findings reveal significant changes in respiratory care practices between 2009 and 2019. Despite an increase in use of non-invasive respiratory strategies, BPD-free survival did not improve and even worsened in the group with the lowest GA (230-256).
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Displasia Broncopulmonar/terapia , Ventilação com Pressão Positiva Intermitente/tendências , Respiração com Pressão Positiva/tendências , Síndrome do Desconforto Respiratório do Recém-Nascido/terapia , Humanos , Recém-Nascido , Doenças do Prematuro/terapia , Estudos Retrospectivos , Espanha , Análise de SobrevidaRESUMO
After the publication of the recommendations, agreed by all the scientific societies through the ILCOR, at the end of 2020, the GRN-SENeo began a process of analysis and review of the main changes since the last guidelines, to which a specific consensus positioning on controversial issues, trying to avoid ambiguities and trying to adapt the evidence to our environment. This text summarizes the main conclusions of this work and reflects the positioning of that group.
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Ressuscitação , ConsensoRESUMO
Introduction: While non-invasive positive-pressure ventilation (NIPPV) is increasingly used as a mode of respiratory support for preterm infants, it remains unclear whether this technique translates into improved respiratory outcomes. We assessed the association between NIPPV use and bronchopulmonary dysplasia (BPD)-free survival in never intubated very preterm infants. Methods: This multicenter cohort study analyzed data from the Spanish Neonatal Network SEN1500 corresponding to preterm infants born at <32 weeks gestational age and <1,500 g and not intubated during first admission. The exposure of interest was use of NIPPV at any time and the main study outcome was survival without moderate-to-severe BPD. Analyses were performed both by patients and by units. Primary and secondary outcomes were compared using multilevel logistic-regression models. The standardized observed-to-expected (O/E) ratio was calculated to classify units by NIPPV utilization and outcome rates were compared among groups. Results: Of the 6,735 infants included, 1,776 (26.4%) received NIPPV during admission and 6,441 (95.6%) survived without moderate-to-severe BPD. After adjusting for confounding variables, NIPPV was not associated with survival without moderate-to-severe BPD (OR 0.84; 95%CI 0.62-1.14). A higher incidence of moderate-to-severe BPD-free survival was observed in high- vs. very low-utilization units, but no consistent association was observed between O/E ratio and either primary or secondary outcomes. Conclusion: NIPPV use did not appear to decisively influence the incidence of survival without moderate-to-severe BPD in patients managed exclusively with non-invasive ventilation.
RESUMO
After the publication of the recommendations, agreed by all the scientific societies through the ILCOR, at the end of 2020, the GRN-SENeo began a process of analysis and review of the main changes since the last guidelines, to which a specific consensus positioning on controversial issues, trying to avoid ambiguities and trying to adapt the evidence to our environment. This text summarizes the main conclusions of this work and reflects the positioning of that group.
RESUMO
AIM: To develop and validate a feasible predictive model for early surfactant treatment in very preterm infants (VPI) admitted with respiratory distress syndrome (RDS). METHODS: Preterm infants less than 32 weeks of gestation with RDS and stabilized with noninvasive ventilation in delivery room were recruited (January 2018-April 2020). Clinical data, chest X-ray (CXR) score, respiratory support, oxygen saturation/fraction of inspired oxygen ratio (SF ratio), lung ultrasound (LUS) score, and diaphragmatic thickening fraction (DTF) were recorded at 60-120 min of life. Oxygen threshold for surfactant administration was fraction of inspired oxygen more than 30%; ultrasound findings were blinded. Logistic regression models using a stepwise selection of variables were developed in the derivation cohort. Coefficients from these models were applied to the validation cohort and a diagnostic performance was calculated. RESULTS: A total of 144 VPI with a mean gestational age of 28.7 ± 2.2 weeks were included (94 into the derivation cohort, 50 into the validation cohort); 37 required surfactant treatment (25.7%). Gestational age, SF ratio, LUS score, CXR score, and Silverman score were related to surfactant administration (R2 = .823). Predictors included in the final model for surfactant administration were SF ratio and LUS score (R2 = .783) with an area under the receiver operating characteristic (AUC) = 0.97 (95% confidence interval [CI]: 0.93-1.00) in the derivation cohort and an AUC = 0.95 (95% CI: 0.85-0.99) in the validation cohort. By applying our predictive model, 26 patients (70.2%) would have been treated with surfactant earlier than 2 h of life. CONCLUSION: The predictive model showed a high diagnostic performance and could be of value to optimize early respiratory management in VPI with RDS.
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Surfactantes Pulmonares/uso terapêutico , Síndrome do Desconforto Respiratório do Recém-Nascido/diagnóstico por imagem , Síndrome do Desconforto Respiratório do Recém-Nascido/tratamento farmacológico , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Modelos Logísticos , Pulmão/diagnóstico por imagem , Masculino , Reprodutibilidade dos Testes , UltrassonografiaRESUMO
We would like to thank Gounaris et al [...].
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Lactente Extremamente Prematuro , Doenças do Prematuro , Humanos , Lactente , Recém-Nascido , Recém-Nascido de muito Baixo Peso , Nutrientes , Política NutricionalAssuntos
Salas de Parto , Ressuscitação , Recém-Nascido , Gravidez , Humanos , Criança , Feminino , Ressuscitação/métodos , Inquéritos e Questionários , AlgoritmosRESUMO
INTRODUCTION: Pulmonary atresia with intact ventricular septum and critical pulmonary stenosis in newborns encompasses a wide spectrum of disease, including cases with significant right ventricular hypoplasia and coronary artery to right ventricle fistulae, which may be considered a contraindication for decompression of the right ventricle. The aim of this study was to review the middle- and long-term outcomes of these patients over 20 years and identify differential factors between both groups, including patients with coronary artery fistulae. PATIENTS AND METHODS: We performed a descriptive retrospective study by identifying all patients that received a diagnosis of pulmonary atresia with intact ventricular septum and critical pulmonary stenosis between January 1996 and January 2018. We collected and analysed data regarding right ventricular morphology, surgical management, percutaneous intervention and medium- and long-term outcomes. RESULTS: 51 patients were admitted. A total of 9 patients (17.6%) died during the followup. None of the deceased patients had coronary artery to right ventricle fistulae. The median length of follow up in the 42 survivors was 8.9 years (1-16). The functional class based on the latest revision of the New York Heart Association classification was 1.2 for the overall sample. Survivors of critical pulmonary stenosis had a functional class of 1.1, and survivors of pulmonary atresia with intact ventricular septum a functional class of 1.6. There were no differences based on the presence or absence of coronary artery to right ventricle fistulae. CONCLUSIONS: Coronary artery to right ventricle fistulae may not be a contraindication for biventricular strategy. Patients with critical pulmonary stenosis had better outcomes compared to patients with pulmonary atresia with intact ventricular septum. The aggressive strategy of opening the pulmonary valve early on was associated with a good overall survival and correlated to a good functional class.
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Cardiopatias Congênitas/cirurgia , Intervenção Coronária Percutânea/métodos , Atresia Pulmonar/cirurgia , Estenose da Valva Pulmonar/cirurgia , Feminino , Seguimentos , Humanos , Recém-Nascido , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
AIM: To analyze different methods to assess postnatal growth in a cohort of very premature infants (VPI) in a clinical setting and identify potential early markers of growth failure. METHODS: Study of growth determinants in VPI (≤32 weeks) during hospital stay. Nutritional intakes and clinical evolution were recorded. Growth velocity (GV: g/kg/day), extrauterine growth restriction (%) (EUGR: weight < 10th centile, z-score < -1.28) and postnatal growth failure (PGF: fall in z-score > 1.34) at 36 weeks postmenstrual age (PMA) were calculated. Associations between growth and clinical or nutritional variables were explored (linear and logistic regression). RESULTS: Sample: 197 VPI. GV in IUGR patients was higher than in non-IUGRs (28 days of life and discharge). At 36 weeks PMA 66.0% of VPIs, including all but one of the IUGR patients, were EUGR. Prevalence of PGF at the same time was 67.4% (IUGR patients: 48.1%; non-IUGRs: 70.5% (p = 0.022)). Variables related to PGF at 36 weeks PMA were initial weight loss (%), need for oxygen and lower parenteral lipids in the first week. CONCLUSIONS: The analysis of z-scores was better suited to identify postnatal growth faltering. PGF could be reduced by minimising initial weight loss and assuring adequate nutrition in patients at risk.
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Insuficiência de Crescimento/diagnóstico , Transtornos do Crescimento/diagnóstico , Transtornos da Nutrição do Lactente/diagnóstico , Doenças do Prematuro/diagnóstico , Recém-Nascido Prematuro , Recém-Nascido de muito Baixo Peso , Estado Nutricional , Antropometria , Estatura , Peso Corporal , Estudos de Coortes , Insuficiência de Crescimento/terapia , Feminino , Retardo do Crescimento Fetal , Idade Gestacional , Transtornos do Crescimento/terapia , Humanos , Lactente , Transtornos da Nutrição do Lactente/terapia , Recém-Nascido , Doenças do Prematuro/terapia , Unidades de Terapia Intensiva Neonatal , Tempo de Internação , Modelos Logísticos , Estudos Longitudinais , Masculino , Avaliação Nutricional , Oxigênio , Nutrição Parenteral , Redução de PesoRESUMO
The International Liaison Committee on Resuscitation (ILCOR) recommendations provide a universal guide of measures to support the transition and resuscitation of newborn after their birth. This guide is expected to be adapted by local groups or committees on resuscitation, according to their own circumstances. The objective of this review is to analyse the main changes, to discuss several of the controversies that have appeared since 2010, and contrasting with other national and international organisations, such as European Resuscitation Council (ERC), American Heart Association (AHA), or the Australian-New Zealand Committee on Resuscitation (ANZCOR). Thus, the Neonatal Resuscitation Group of the Spanish Society of Neonatology (GRN-SENeo) aims to give clear answers to many of the questions when different options are available, generating the forthcoming recommendations of our country to support the transition and/or resuscitation of a newborn after birth, safely and effectively.
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Ressuscitação/normas , Algoritmos , Humanos , Recém-Nascido , InternacionalidadeRESUMO
OBJECTIVES: To assess the kinetics of procalcitonin (PCT) and C-reactive protein (CRP) in newborns after cardiothoracic surgery (CS), with and without cardiopulmonary bypass, and to assess whether PCT was better than CRP in identifying sepsis in the first 72 hours after CS. PATIENTS AND METHODS: This is a prospective study of newborns admitted to the neonatal intensive care unit after CS. INTERVENTIONS: PCT and CRP were sequentially drawn 2 hours before surgery and at 0, 12, 24, 48, and 72 hours after surgery. RESULTS: A total of 65 patients were recruited, of which 14 were excluded because of complications. We compared the kinetics of PCT and CRP after CS in bypass and non-bypass groups without sepsis; there were no differences in the PCT values at any time (24 hours, P = 0.564; 48 hours, P = 0.117; 72 hours, P = 0.076). Thirty-five patients needed bypass, of whom four were septic (11.4%). Significant differences were detected in the PCT values on comparing the septic group to the nonseptic group at 48 hours after cardiopulmonary bypass (P = 0.018). No differences were detected in the CRP values in these groups. A suitable cutoff for sepsis diagnosis at 48 hours following bypass would be 5 ng/mL, with optimal area under the curve of 0.867 (confidence interval 0.709-0.958), P < 0.0001, and sensitivity and specificity of 87.5% (29.6-99.7) and 72.6% (53.5-86.4), respectively. CONCLUSION: This is a preliminary study but PCT seems to be a good biomarker in newborns after CS. Values over 5 ng/mL at 48 hours after CS should alert physicians to the high risk of sepsis in these patients.