Jamil Pedro de Siqueira Caldas

Accuracy of white blood cell count, C-reactive protein, interleukin-6 and tumor necrosis factor alpha for diagnosing late neonatal sepsis

OBJECTIVE To evaluate the diagnostic value for late neonatal sepsis of white blood cell count (WBC) and assays for C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha), in isolation and in conjunction. METHODS This was a diagnostic test validation study. Chemiluminescence was used to assay CRP, IL-6 and TNF-alpha at the time of clinical suspicion and again after 24 and 48 hours, whereas the WBC was performed only once, at the time of suspicion. Patients were classified into three groups based on clinical progress and culture results: confirmed sepsis (CS), probable sepsis (PS), and not infected (NI). Statistical analysis was performed using the Wilcoxon and chi-square tests and Friedman analysis of variance; cutoffs were defined by plotting receiver operator characteristic curves. RESULTS The total study sample comprised 82 children, 42 of whom were classed as CS, 16 as PS and 24 as NI. At all three test times, the medians for CRP and IL-6 were significantly more elevated in the CS and PS groups, while the medians for TNF-alpha were abnormal only in the CS group. The CRP test had elevated indices of diagnostic utility at all three test times, better accuracy than the WBC and similar accuracy to the first IL-6 and TNF-alpha assays. There was no statistical difference between the cytokines, nor between them and the WBC. Combining tests did not increase diagnostic power, with the exception of the combination of WBC with CRP2 and when the sequential CRP assays were combined. CONCLUSIONS Both CRP and WBC were useful for the diagnosis of late neonatal sepsis and comparable with IL-6 and TNF-alpha. Accuracy increased when CRP and WBC were combined and when sequential CRP assay results were used.

Epileptic manifestations induced by midazolam in the neonatal period

Antiepileptic drugs may cause worsening of epilepsy by aggravating pre-existing seizures or by triggering new seizure types. There are several reports of adverse effects related to midazolam, but only a few authors reported epileptic manifestations. We report four newborns seen at the Neonatal Intensive Care Unit of our University Hospital, who developed seizures a few seconds after the administration of midazolam. It is difficult to identify the patients at risk, but it is important to be aware and recognize this situation.

Acurácia diagnóstica do leucograma, proteína C-reativa, interleucina-6 e fator de necrose tumoral-alfa na sepse neonatal tardia

OBJETIVO: Avaliar o valor do leucograma, proteina C-reativa (PCR), interleucina-6 (IL-6) e do fator de necrose tumoral-alfa (TNF-α), isoladamente e em conjunto, na deteccao da sepse neonatal tardia. METODOS: Estudo de validacao diagnostica. A PCR, IL-6 e TNF-α foram dosados por quimioluminescencia a suspeita clinica, 24 e 48 horas depois, e o leucograma unicamente a suspeita. De acordo com evolucao clinica e resultados de culturas, tres grupos foram definidos: sepse comprovada (SC), sepse provavel (SP) e nao infectados (NI). Os testes estatisticos utilizados foram os de Wilcoxon, qui-quadrado e analise de variância de Friedman e os limites de corte foram obtidos pela construcao da curva ROC. RESULTADOS: Estudaram-se 82 criancas, sendo 42 no grupo SC, 16 no SP e 24 NI. Nos tres momentos, as medianas da PCR e da IL-6 mostraram-se significativamente mais elevadas nos grupos SC e SP, e as do TNF-α alteraram-se apenas no grupo SC. Os indices diagnosticos da PCR foram elevados nos tres momentos e com acuracia superior a do leucograma e semelhante a da IL-6 e a do TNF-α em suas primeiras medidas. Entre as citocinas, nao houve diferenca estatistica entre elas, nem em relacao ao leucograma. A associacao dos testes nao aumentou a capacidade diagnostica, exceto na combinacao entre leucograma e PCR2 e na dosagem seriada de PCR. CONCLUSOES: A PCR e o leucograma mostram-se uteis no diagnostico de sepse neonatal tardia e comparaveis a IL-6 e ao TNF-α. A acuracia aumentou com a associacao PCR-leucograma e a dosagem seriada da PCR.

Antenatal maternal corticosteroid administration and markers of oxidative stress and inflammation in umbilical cord blood from very low birth weight preterm newborn infants

OBJECTIVE To investigate the association between antenatal maternal corticosteroid administration and blood levels of reactive oxygen intermediates (ROI), reduced glutathione (GR) and interleukin-6 (IL-6) in preterm, very low birth weight infants. METHODS This was a cohort study in which cord blood samples were used for the following tests: baseline and stimulated granulocyte ROI were measured by flow cytometry; GR was assayed by spectrophotometry; and IL-6 by enzyme-linked immunosorbent assay. Two different comparative analyses of antenatal corticosteroid (betamethasone) were conducted: the first compared administration against no administration and the second compared mothers who received the complete cycle with those given only a partial antenatal corticosteroid cycle. Maternal and neonatal variables were analyzed in order to compare groups. Categorical variables were compared using the chi-square or Fischer tests, and blood marker test results were compared using the Mann-Whitney test. RESULTS The different corticoid therapy groups were similar in terms of all of the maternal and neonatal variables with the exception of vaginal delivery, which was significantly associated with not receiving antenatal corticosteroid. The results for ROI, GR and IL-6 did not differ when the comparison was based on simple presence or absence of administration of the steroid. However, when the complete cycle was compared against incomplete administration, median ROI and IL-6 were lower among those given the complete cycle. CONCLUSION Administration of the complete cycle of betamethasone to the mother had a suppressive effect on baseline ROI and IL-6 production in very low birth weight preterm newborn infants.

Death or survival with major morbidity in VLBW infants born at Brazilian neonatal research network centers

Abstract Objective: To analyze unfavorable outcomes at hospital discharge of preterm infants born at Brazilian public university centers. Methods: Prospective cohort of 2646 inborn infants with gestational age 23–33 weeks and birth weight 400–1499 g, without malformations, born at 20 centers in 2012–2013. Unfavorable outcome was defined as in-hospital death or survival at hospital discharge with ≥1 major morbidities: bronchopulmonary dysplasia (BPD) at 36 corrected weeks, intraventricular hemorrhage (IVH) grades 3–4, periventricular leukomalacia (PVL) or surgically treated retinopathy of prematurity (ROP). Results: Among 2646 infants, 1390 (53%) either died or survived with major morbidities: 793 (30%) died; 497 (19%) had BPD; 358 (13%) had IVH 3–4 or PVL; and 84 (3%) had ROP. Logistic regression adjusted by center showed association of unfavorable outcome with: antenatal steroids (OR 0.70; 95%CI 0.55–0.88), C-section (0.72; 0.58–0.90), gestational age <30 (4.00; 3.16–5.07), being male (1.44; 1.19–1.75), small for gestational age (2.19; 1.72–2.78), 5th-min Apgar <7 (3.89; 2.88–5.26), temperature at NICU admission <36.0 °C (1.42; 1.15–1.76), respiratory distress syndrome (3.87; 2.99–5.01), proven late sepsis (1.33; 1.05–1.69), necrotizing enterocolitis (3.10; 2.09–4.60) and patent ductus arteriosus (1.69; 1.37–2.09). Conclusions: More than half of the VLBW infants born at public university level 3 Brazilian hospitals either die or survive with major morbidities.

Incidência de hemorragia peri-intraventricular em recém-nascidos de muito baixo peso: análise de 15 anos

OBJECTIVE: To assess the incidence of periventricular/intraventricular hemorrhage (PIVH) in very low birth rate neonates. METHODS: This was a prospective cohort study conducted on a sample of very low birth weight infants over a 15-year period. Neonates who did not undergo cerebral ultrasonography, had malformations affecting the central nervous system, or died within the first 24 hours of life were excluded. Ultrasonography was performed through the anterior fontanelle using an Aloka® 620 scanner with a 5 mHz probe, between days 1 and 3 of life, at 7 days, and at 28 days (or at discharge). Incidence was analyzed by means of the chi-square test for trend or Cochran-Armitage test and through a simple linear regression model with a logarithmic trendline as the output. For assessment of potential associated factors, a variety of obstetric, perinatal, and neonatal data collected between 1991-1994 and 2002-2005 were analyzed, using the chi-square and Fishers exact tests for statistical analysis. The significance level was set at 5%. RESULTS: Of 1,777 very low birth weight infants born during the study period, 1,381 (77.7%) were examined. Of these, 289 (20.9%) had PIVH. The yearly distribution of cases showed a progressive decline in incidence, from 50.9% in 1991 to 11.9% in 2005 (p < 0.0001). The incidence of PIVH decreased across all weight ranges as well as at grades I/II and III/IV. Significant differences in antenatal corticosteroid use, gender (male), weight (< 1,000 g), hyaline membrane disease, mechanical ventilation, administration of surfactant, patent ductus arteriosus, and sepsis were found. CONCLUSION: The incidence of PIVH in very low birth weight infants declined significantly during the study period.

Incidence of periventricular/intraventricular hemorrhage in very low birth weight infants: a 15-year cohort study.

OBJECTIVE To assess the incidence of periventricular/intraventricular hemorrhage (PIVH) in very low birth rate neonates. METHODS This was a prospective cohort study conducted on a sample of very low birth weight infants over a 15-year period. Neonates who did not undergo cerebral ultrasonography, had malformations affecting the central nervous system, or died within the first 24 hours of life were excluded. Ultrasonography was performed through the anterior fontanelle using an Aloka® 620 scanner with a 5 mHz probe, between days 1 and 3 of life, at 7 days, and at 28 days (or at discharge). Incidence was analyzed by means of the chi-square test for trend or Cochran-Armitage test and through a simple linear regression model with a logarithmic trendline as the output. For assessment of potential associated factors, a variety of obstetric, perinatal, and neonatal data collected between 1991-1994 and 2002-2005 were analyzed, using the chi-square and Fishers exact tests for statistical analysis. The significance level was set at 5%. RESULTS Of 1,777 very low birth weight infants born during the study period, 1,381 (77.7%) were examined. Of these, 289 (20.9%) had PIVH. The yearly distribution of cases showed a progressive decline in incidence, from 50.9% in 1991 to 11.9% in 2005 (p < 0.0001). The incidence of PIVH decreased across all weight ranges as well as at grades I/II and III/IV. Significant differences in antenatal corticosteroid use, gender (male), weight (< 1,000 g), hyaline membrane disease, mechanical ventilation, administration of surfactant, patent ductus arteriosus, and sepsis were found. CONCLUSION The incidence of PIVH in very low birth weight infants declined significantly during the study period.

Peri-intraventricular hemorrhage and oxidative and inflammatory stress markers in very-low birth weight newborns

OBJECTIVES To evaluate the association between oxidative and inflammatory stress markers with peri-intraventricular hemorrhage (PIVH) in very-low birth weight newborns. METHODS This was a prospective study conducted in a level III neonatal unit. Basal and stimulated reactive oxygen intermediates (ROIs), reduced glutathione (GSH), and interleukin-6 (IL-6) levels were measured in umbilical cord blood. Newborns underwent serial ultrasound at the bedside, at 6, 12, 24, and 72hours of life and at seven days for the diagnosis of PIVH, classified as grades I to IV. Two groups were assessed, those with and without PIVH; maternal and neonatal control variables were used for comparison. Univariate and multiple regression analyses were applied. RESULTS A total of 125 newborns were assessed. PIVH incidence rate was 12.0%. In the univariate analysis, basal ROI, the use of two or more doses of corticosteroids, birth weight<1,000g, ventilatory support use, and SNAPPE II value ≥ 22 were significantly associated with PIVH. However, in the multivariate analysis, only antenatal steroid use was independently associated with the disease (OR 0,194; 95% CI: 0,048 to 0,773; p=0,02). CONCLUSION ROI, GSH, and IL-6 levels were not associated with the occurrence of PIVH in very-low birth weight infants.

Acute liver failure in a term neonate after repeated paracetamol administration

Objective: Severe hepatotoxicity caused by paracetamol is rare in neonates. We report a case of paracetamol-induced acute liver failure in a term neonate. Case description: A 26-day-old boy was admitted with intestinal bleeding, shock signs, slight liver enlargement, coagulopathy, metabolic acidosis (pH=7.21; bicarbonate: 7.1mEq/L), hypoglycemia (18mg/dL), increased serum aminotransferase activity (AST=4,039IU/L; ALT=1,087IU/L) and hyperbilirubinemia (total: 9.57mg/dL; direct: 6.18mg/dL) after receiving oral paracetamol (10mg/kg/dose every 4 hours) for three consecutive days (total dose around 180mg/kg; serum concentration 36-48 hours after the last dose of 77µg/ mL). Apart from supportive measures, the patient was successfully treated with intravenous N-acetylcysteine infusion during 11 consecutive days, and was discharged on day 34. The follow-up revealed full recovery of clinical and of laboratory findings of hepatic function. Comments: The paracetamol pharmacokinetics and pharmacodynamics in neonates and infants differ substantially from those in older children and adults. Despite the reduced rates of metabolism by the P-450 CYP2E1 enzyme system and the increased ability to synthesize glutathione - which provides greater resistance after overdoses -, it is possible to produce hepatotoxic metabolites (N-acetyl-p-benzoquinone) that cause hepatocellular damage, if glutathione sources are depleted. Paracetamol clearance is reduced and the half-life of elimination is prolonged. Therefore, a particular dosing regimen should be followed due to the toxicity risk of cumulative doses. This report highlights the risk for severe hepatotoxicity in neonates after paracetamol multiple doses for more than two to three days.Objetivo: A hepatoxicidade grave induzida pelo paracetamol e muito rara em neonatos. Relata-se o caso de um neonato de termo que desenvolveu falencia hepatica aguda apos o uso de paracetamol. Descricao do caso: Menino, 26 dias, admitido com sangramento intestinal, sinais de choque, discreta hepatomegalia, coagulopatia, acidose metabolica (pH=7,21; bicarbonato: 7,1mEq/L), hipoglicemia (18mg/dL), aumento das aminotransferases sericas (AST=4.039UI/L; ALT=1.087UI/L) e hiperbilirrubinemia (total: 9,57mg/dL; direta: 6,18mg/dL), apos uso de paracetamol via oral (10mg/kg/dose a cada quatro horas) por tres dias consecutivos (dose total ao redor de 180mg/kg; nivel serico de 36-48 horas apos a ultima dose de 77µg/mL). Alem das medidas de suporte, o paciente foi tratado com N-acetilcisteina (infusao intravenosa continua por 11 dias consecutivos), recebendo alta apos 34 dias de internacao. O seguimento mostrou recuperacao clinica e dos parâmetros laboratoriais da funcao hepatica. Comentarios: A farmacocinetica e a farmacodinâmica do paracetamol em neonatos e lactentes jovens (menores de um ano) diferem substancialmente de criancas maiores e adultos. Apesar de as taxas de metabolismo do sistema enzimatico P-450 CYP2E1 estarem diminuidas e a capacidade de gerar glutationa, aumentadas - conferindo maior protecao apos superdosagens -, existe a possibilidade de producao de metabolitos hepatotoxicos (N-acetil-p-benzoquinoneimina) que determinam lise celular, caso se esgotem as reservas de glutationa. A depuracao e diminuida e a meia-vida de eliminacao e prolongada, recomendando-se posologia distinta pelo risco de toxicidade de doses cumulativas. O presente relato destaca o risco de hepatotoxicidade grave em neonatos apos o uso continuo de paracetamol por mais de dois a tres dias.

T-piece versus self-inflating bag ventilation in preterm neonates at birth

Objective To verify whether the use of the T-piece resuscitator compared with the self-inflating bag in preterm infants ventilated at birth modifies survival to hospital discharge without major morbidities. Design Pragmatic prospective cohort study. Setting 20 Brazilian university hospitals of Brazilian Network on Neonatal Research. Patients were 1962 inborn infants in 2014–2015 ventilated at birth with 23–33’ weeks gestation and birth weight 400–1499 g without malformations. Patients transferred until the 27th day after birth were excluded. Interventions Positive pressure ventilation at birth with T-piece resuscitator or self-inflating bag without positive end expiratory pressure valve. Intervention with ventilation followed the Brazilian Society of Pediatrics guidelines. The choice of the equipment was at the neonatologist’s discretion in each delivery. The main outcome measures were survival to hospital discharge without bronchopulmonary dysplasia, severe peri-intraventricular haemorrhage and periventricular leucomalacia. Logistic regression adjusted for confounding variables was applied for main outcome. Results 1456 (74%) were only ventilated with T-piece resuscitator and 506 (26%) with the self-inflating bag. The characteristics of those ventilated with T-Piece resuscitator versus self-inflating bag were birth weight 969 ± 277 vs 941 ± 279 g, gestational age 28.2±2.5 vs 27.8±2.7 weeks and survival to hospital discharge without major morbidities 47% vs 35%. Logistic regression adjusted for maternal characteristics, obstetric and neonatal morbidities showed that the T-piece resuscitator increased the chance of survival to hospital discharge without major morbidities (OR=1.38; 95% CI 1.06 to 1.80; Hosmer-Lemeshow goodness of fit: 0.695). Conclusion This study is the first that highlights the effectiveness of T-piece resuscitator ventilation in improving relevant outcomes in preterm neonates.