Plasma concentrations of levobupivacaine in neonates during caudal epidural analgesia maintained over 48 hours.

BACKGROUND: Differences in neonatal pharmacokinetics are known to cause systemic accumulation of levobupivacaine with adverse effects during epidural analgesia. Therefore, it is not recommended to surpass 48 hours of administration in neonates. Free and total levobupivacaine levels are considered as predictors of toxicity. OBJECTIVE: The aim of the LEVON pilot study was to detect the accumulation of levobupivacaine during epidural analgesia exceeding 48 hours in neonates. METHODS: Ten neonates received a loading dose of levobupivacaine (1.25 mg/kg) followed by a continuous infusion (0.2 mg/kg/hour) epidurally. Free and total levobupivacaine concentrations were measured 0.5, 1, 6, 12, 36, 72 and 144 hours after the start of infusion. Cumulative doses of levobupivacaine, pain scores and clinical signs of toxicity were used for assessing efficacy and safety. RESULTS: The median concentrations of total levobupivacaine were 586.0, 563.0, 837.5, 957.0, 1930.0, 708.5 and 357.5 ng/ml. The median concentrations of free levobupivacaine were 4.0, 3.6, 5.5, 3.6, 5.5, 0.8 and 0.0 ng/ml. Three patients reached concerning concentrations of total levobupivacaine. Levels of free levobupivacaine remained low. No signs of toxicity were observed. CONCLUSION: Caudal epidural analgesia with levobupivacaine lasting longer than 48 hours appears to be safe providing that free levobupivacaine levels are below the presumed threshold for toxicity (Tab. 1, Fig. 1, Ref. 29). Text in PDF www.elis.sk Keywords: free levobupivacaine, total levobupivacaine, neonate, caudal continuous epidural analgesia, postoperative pain.

Bacterial DNA detection in very preterm infants assessed for risk of early onset sepsis.

OBJECTIVES: The aim of this study is to evaluate the diagnostic ability of multiplex real-time polymerase chain reaction (PCR) in very preterm infants assessed for risk of early onset neonatal sepsis (EOS). METHODS: Prospective observational cohort study. Blood samples of preterm neonates ≤32 weeks of gestation were evaluated by commercial multiplex real-time PCR within 2 h after delivery. The definition of EOS was based on positive blood culture and clinical signs of infection or negative blood culture, clinical signs of infection and abnormal neonatal blood count and serum biomarkers. RESULTS: Among 82 subjects analyzed in the study, 15 had clinical or confirmed EOS. PCR was positive in four of these infants (including the only one with a positive blood culture), as well as in 15 of the 67 infants without sepsis (sensitivity 27%, specificity 78%). Out of 19 PCR positive subjects, Escherichia coli was detected in 12 infants (63%). Statistically significant association was found between vaginal E. coli colonization of the mother and E. coli PCR positivity of the neonate (p=0.001). No relationship was found between neonatal E. coli swab results and assessment findings of bacterial DNA in neonatal blood stream. CONCLUSIONS: Multiplex real-time PCR had insufficient diagnostic capability for EOS in high risk very preterm infants. The study revealed no significant association between PCR results and the diagnosis of clinical EOS. Correlation between maternal vaginal swab results and positive PCR in the newborn needs further investigation to fully understand the role of bacterial DNA analysis in preterm infants.

Role of umbilical interleukin-6, procalcitonin and C-reactive protein measurement in the diagnosis of fetal inflammatory response syndrome.

OBJECTIVE: Fetal Inflammatory Response Syndrome (FIRS) is a serious complication accompanied by increased neonatal mortality and morbidity. Early dia-gnosis of FIRS is essential to detect high risk infants. The aim of the study was to evaluate the correlation between interleukin-6 (IL-6), procalcitonin (PCT), C-reactive protein (CRP) in cord blood and histologically proven funisitis;chorioamnionitis in high-risk infants after preterm birth. METHODS: Blood sampling for the measurement of inflammatory bio-markers was performed immediately after placental delivery and umbilical cutting. Umbilical and placental inflammatory changes were assessed using a recently released scoring system (Amsterdam Placental Workshop Group Consensus). RESULTS: One hundred preterm infants (30.5 ± 2.5 gestational week, birth weight 1,443 ± 566 grams) and 21 health term infants were analyzed. Histologic chorioamnionitis was confirmed in 19% cases and chorioamnionitis with funisitis in 7% cases. Thirty-three infants (33%) fulfilled criteria of FIRS (funistis and/ or umbilical IL-6 > 11 ng/ L). The presence of FIRS correlated significantly with maternal leukocytosis (P < 0.001), preterm premature rupture of membrane (P < 0.001) and preterm uterine contraction (P < 0.0001). In comparison to preterm and healthy term infants we found statistically significant higher levels of umbilical inflammatory bio­markers (IL-6, PCT, CRP) in FIRS group (P < 0.0001). Composite mortality and morbidity (bronchopulmonary dysplasia, intraventricular haemorrhage, periventricular leukomalacia) was higher in FIRS group (28.1 vs 22.4% in preterm group). However, the difference was not statistically significant (P = 0.53). CONCLUSION: Our study confirmed the correlation of umbilical inflammatory bio­markers levels (IL-6, PCT, CRP) and the presence of FIRS. We did not find significant adverse impact of FIRS on neonatal mortality and morbidity. Nevertheless, our results could be influenced by the size of study group and strict inclusion criteria (only cases after C-section were analyzed).

Does perinatal management have the potential to reduce the risk of intraventricular hemorrhage in preterm infants?

Background: Intraventricular hemorrhage (IVH) is an important cause of neurodevelopmental impairment in preterm infants. A number of risk factors for IVH have already been proposed; however, some controversies regarding optimal perinatal management persist. This study aimed to identify perinatal and neonatal attributes associated with IVH in a representative population of preterm infants. Methods: Perinatal data on 1,279 very preterm infants (<32 weeks of gestation) admitted to a tertiary neonatal intensive care unit were analyzed. The records were assessed using univariate analysis and logistic regression model to evaluate the risk factors for any and high-grade IVH (grade III-IV according to the classification by Papile) within the first week after birth. Results: The incidence of any IVH was 14.3% (183/1,279); the rate of low-grade (I-II) and high-grade (III-IV) IVH was 9.0% (115/1,279) and 5.3% (68/1,279), respectively. Univariate analysis revealed multiple factors significantly associated with intraventricular hemorrhage: lower gestational age and birth weight, absence of antenatal steroids, vaginal delivery, low Apgar score at 5 min, delivery room intubation, surfactant administration, high frequency oscillation, pulmonary hypertension, pulmonary hemorrhage, tension pneumothorax, persistent ductus arteriosus, hypotension and early onset sepsis. Logistic regression confirmed lower gestational age, vaginal delivery, ductus arteriosus and early onset sepsis to be independent predictors for any IVH. Pulmonary hemorrhage, tension pneumothorax and early onset sepsis were independent risk factors for high-grade IVH. Complete course of antenatal steroids was associated with a lower risk for any (odds ratio 0.58, 95% confidence interval 0.39-0.85; P = .006) and for high-grade intraventricular hemorrhage (odds ratio 0.36, 95% confidence interval 0.20-0.65; P < .001). Conclusion: The use of antenatal steroids and mode of delivery are crucial in the prevention of IVH; however, our study did not confirm the protective effect of placental transfusion. Severe respiratory insufficiency and circulatory instability remain to be powerful contributors to the development of IVH. Early detection and management of perinatal infection may also help to reduce the rate of brain injury and improve neurodevelopment in high-risk newborns.

Serial Measurement of Interleukin-6 Enhances Chance to Exclude Early-Onset Sepsis in Very Preterm Infants.

The aim of this retrospective study was to evaluate the reliability of peak interleukin-6 (IL-6) level within 24 hours after delivery as a predictor for early-onset sepsis (EOS) in very preterm neonates. Interleukin-6 was assessed at 2 hours and at 12 to 24 hours after delivery. The highest level was considered a peak value. The definition of EOS was based on positive blood culture and clinical signs of infection or negative blood culture, clinical signs of infection, and C-reactive protein >10 mg/L. Among 445 enrolled infants, 53 developed EOS. A peak IL-6 level of more than 200 ng/L had a sensitivity of 89% and specificity of 77% for the presence of EOS. The negative predictive value was 98%. Receiver operating characteristics curve had area under the curve of 0.92. Peak IL-6 is a reliable marker of systemic inflammatory response and might be useful to exclude EOS within the first 24 hours.

Neonatal Sequential Organ Failure Assessment (nSOFA) Score within 72 Hours after Birth Reliably Predicts Mortality and Serious Morbidity in Very Preterm Infants.

The aim of this study was to assess the applicability of the neonatal sequential organ failure assessment score (nSOFA) within 72 h after delivery as a predictor for mortality and adverse outcome in very preterm neonates. Inborn neonates <32 weeks of gestation were evaluated. The nSOFA scores were calculated from medical records in the first 72 h after birth and the peak value was used for analysis. Death or composite morbidity at hospital discharge defined the adverse outcome. Composite morbidity consisted of chronic lung disease, intraventricular haemorrhage ≥grade III, periventricular leukomalacia and necrotizing enterocolitis. Among 423 enrolled infants (median birth weight 1070 g, median gestational age 29 weeks), 27 died and 91 developed composite morbidity. Death or composite morbidity was associated with organ dysfunction as assessed by nSOFA, systemic inflammatory response, and low birthweight. The score >2 was associated with OR 2.5 (CI 1.39−4.64, p = 0.002) for the adverse outcome. Area under the curve of ROC was 0.795 (95% CI = 0.763−0.827). The use of nSOFA seems to be reasonable for predicting mortality and morbidity in very preterm infants. It constitutes a suitable basis to measure the severity of organ dysfunction regardless of the cause.

C-Reactive Protein, Interleukin-6, and Procalcitonin in Diagnosis of Late-Onset Bloodstream Infection in Very Preterm Infants.

BACKGROUND: Late-onset bloodstream infection (LOBSI) is common in very preterm infants. Early and accurate diagnosis is crucial for prognosis and outcome. We aimed to analyze the accuracy of routinely used inflammatory biomarkers in the diagnosis of LOBSI as compared to uninfected controls. METHODS: In this single-center, retrospective case-control study, interleukin-6 (IL-6), procalcitonin (PCT), and C-reactive protein (CRP) were routinely measured, when infection was clinically suspected. The definition of LOBSI was based on positive blood culture, clinical signs of infection, and onset more than 72 hours after birth. RESULTS: Among 285 enrolled infants, 66 developed LOBSI. IL-6 was superior to other markers, and levels greater than 100 ng/L had a sensitivity of 94% and a specificity of 99% for the presence of LOBSI. Receiver operating characteristic curve of IL-6 had area under the curve of 0.988 (95% CI = 0.975-1.00, P < .001). The negative predictive value of IL-6, CRP, and PCT for optimal cutoff values was 99%, 95%, and 93%, respectively. The logistic regression model of IL-6 > 100 ng/L or CRP > 10 mg/L were successfully predicted LOBSI in 97.9% of cases. CONCLUSIONS: The combination of IL-6 and CRP seems to have great potential in routine rapid diagnosis of LOBSI development. High negative predictive value of all tested markers could encourage the early discontinuation of antibiotic treatment.

Corpus Callosum Growth and Neurodevelopmental Outcome Are Negatively Influenced by Systemic Infection in Very Low-Birth-Weight Infants.

Systemic infection may negatively modulate the development of cerebral white matter and long-term outcome of neonates. We analyzed the growth of corpus callosum (using cranial ultrasonography) and neurodevelopment (Bayley Scales of Infant Development, Third Edition) in 101 very low-birth-weight newborns. We observed significantly reduced corpus callosum length at 3 months of corrected age (44.5 mm vs 47.7 mm, P = .004) and diminished corpus callosum growth (0.07 mm/d vs 0.08 mm/d, P = .028) in infants who experienced systemic infection. The subgroup exhibited inferior neurodevelopmental outcomes with predominant motor impairment. The results suggest that length and growth of corpus callosum might be affected by systemic inflammatory response in preterm newborns. The changes in corpus callosum can contribute to adverse neurodevelopment at 2 years of corrected age. Serial ultrasonographic measurements of the corpus callosum may be suitable to identify preterm infants with increased risk of neurodevelopmental impairment.

Spontaneous Closure of Patent Ductus Arteriosus in Infants ≤1500 g.

OBJECTIVES: Patent ductus arteriosus (PDA) remains a challenging issue in very low birth weight (VLBW) infants, and its management varies widely. Our aim in this study was to document the natural course of ductus arteriosus in a cohort of VLBW infants who underwent conservative PDA management with no medical or surgical intervention. METHODS: A retrospective cohort study conducted in 2 European level-3 neonatal units. RESULTS: A total of 368 VLBW infants were born within the study period. Two hundred and ninety-seven infants were free of congenital malformations or heart defects and survived to hospital discharge. Out of those, 280 infants received truly conservative PDA management. In 237 (85%) of nontreated infants, the PDA closed before hospital discharge. The Kaplan-Meier model was used to document the incidence proportion of PDA closure over time for different gestational age groups. The median time to ductal closure was 71, 13, 8, and 6 days in <26+0, 26+0 to 27+6, 28+0 to 29+6, and ≥30 weeks, respectively. For different birth weight groups, the median was 48, 22, 9, and 8 days in infants weighing <750, 750 to 999, 1000 to 1249, and 1250 to 1500 g, respectively. No statistically significant relationship was found between PDA closure before hospital discharge and neonatal morbidities. CONCLUSIONS: The likelihood of PDA spontaneous closure in VLBW infants is extremely high. We provide in our findings a platform for future placebo-controlled trials focused on the smallest and youngest infants.