Kosmas Sarafidis

Follow-up of very low birth weight infants after erythropoietin treatment to prevent anemia of prematurity

OBJECTIVE Treatment with recombinant human erythropoietin (rHuEPO) stimulates erythropoiesis and reduces the need for transfusions in hospitalized preterm infants. The aim of our study was to follow very low birth weight infants after the initial 6 weeks of rHuEPO treatment. DESIGN AND METHODS We randomly assigned 97 very low birth weight infants with a gestational age of 31 weeks or less and birth weight of 1500 gm or less to receive rHuEPO, 300 units/kg per week (erythropoietin (EPO) 300, n = 33), rHuEPO, 750 units/kg per week (EPO 750; n = 28), or no treatment (control, n = 36). The rHuEPO was administered from the first week of life for 6 weeks. After EPO therapy was discontinued, 75 neonates were followed weekly until discharge and at 3, 6, and 12 months of age. RESULTS Mean numbers (+/- SD) of packed erythrocyte transfusions per patient from the time rHuEPO therapy was discontinued until discharge were 0.38 +/- 0.64 (EPO 300), 0.23 +/- 0.52 (EPO 750), 0.9 +/- 1.1 (control) (p < 0.05 in both EPO groups vs control). Mean reticulocyte counts at the sixth week were 6% +/- 2.2% (EPO 300), 6.9% +/- 2.2% (EPO 750), and 3.1% +/- 2.6% (control) in the three groups (p < 0.01 in both EPO groups vs control), and at the eighth week were 4.7% +/- 2.8% (EPO 300), 5.4% +/- 2.7% (EPO 750), and 2.6% +/- 2.2% (control) (p < 0.01 in both EPO groups vs control). Serum ferritin levels were significantly higher at the sixth week, and the percentage of hemoglobin F was significantly lower at 6, 8, and 10 weeks in the control group versus EPO groups. At 3, 6, and 12 months of age, there were no differences in reticulocytes, ferritin, HbF, and growth among groups. CONCLUSION Preterm infants who received rHuEPO had a normal pattern of erythropoiesis after the drug was discontinued. These data provide strong evidence that the anemia of prematurity is the result of a transient developmental abnormality in EPO production.

Impact of prematurity, stress and sepsis on the neutrophil respiratory burst activity of neonates

The aim of this study was to evaluate the impact of prematurity, sepsis and stress on the neutrophil respiratory burst activity (NRBA) of neonates. For this purpose 122 healthy neonates (89 term and 33 preterm), 33 preterm stressed neonates, 59 septic neonates (12 term and 47 preterm) and 26 healthy adults were studied. The NRBA was assessed after in vitro stimulation by PMA using a whole blood flow cytometric microassay with dihydrorhodamine 123 (DHR 123). It was found that the percentage of responding neutrophils in term neonates was comparable to that found in adults (medians 83.5 and 89.8%, respectively), whereas it was significantly lower in the healthy preterm neonates (median 70.6%, p < 0.05). The NRBA was further depressed in the stressed (median = 63%) and septic neonates, both term and preterm (medians 60.5 and 54.3%, respectively). No correlation with the levels of G-CSF, TNF-alpha and IL-1 beta, which were found to be higher in the stressed and septic neonates, was observed. These findings indicate that prematurity, sepsis and stress significantly depress the respiratory burst activity of neonatal neutrophils.

Administration of recombinant human granulocyte-colony stimulating factor to septic neonates induces neutrophilia and enhances the neutrophil respiratory burst and β2 integrin expression Results of a randomized controlled trial

Abstract The objective of this study was to investigate the effect of treatment with recombinant human granulocyte-colony stimulating factor (rhG-CSF) on the neutrophil count and function of preterm neonates with documented sepsis. For this purpose 62 preterm neonates with proven sepsis and 19 healthy preterm ones were studied. Of the 62 patients, 27 septic neonates had an absolute neutrophil count (ANC) >5000/mm3 (group A) and were scheduled not to receive rhG-CSF and 35/62 had an ANC <5000/mm3 (n= 35) and were randomly assigned either to receive rhG-CSF (group B) or not to receive it (group C). rhG-CSF (10 μg/kg) was administered for 3 consecutive days (0, 1, 2). The ANC, plasma levels of G-CSF (ELISA), neutrophil respiratory burst activity (NRBA) and neutrophil expression of CD11a, CD11b and CD11c (flow cytometry) were measured in all septic neonates on days 0 (onset of sepsis), 1, 3 and 5 and in the healthy neonates once within the first 2 days of life. We found that on day 0, G-CSF levels of all groups of septic neonates were significantly higher than those of the healthy ones. The highest levels were observed in group A. NRBA was diminished only in groups B and C and the expression of CD11a and CD11c was reduced in all groups of septic neonates. Administration of rhG-CSF resulted in a rapid and significant increase in ANC, NRBA and CD11a, CD11b and CD11c expression that persisted throughout the follow up. Conclusion The administration of granulocyte colony stimulating factor to septic neonates significantly increases the absolute granulocyte count and enhances the neutrophil respiratory burst and β2 integrin expression.

Sedation and analgesia practices in neonatal intensive care units (EUROPAIN): results from a prospective cohort study

BACKGROUND Neonates who are in pain or are stressed during care in the intensive care unit (ICU) are often given sedation or analgesia. We investigated the current use of sedation or analgesia in neonatal ICUs (NICUs) in European countries. METHODS EUROPAIN (EUROpean Pain Audit In Neonates) was a prospective cohort study of the management of sedation and analgesia in patients in NICUs. All neonates admitted to NICUs during 1 month were included in this study. Data on demographics, methods of respiration, use of continuous or intermittent sedation, analgesia, or neuromuscular blockers, pain assessments, and drug withdrawal syndromes were gathered during the first 28 days of admission to NICUs. Multivariable linear regression models and propensity scores were used to assess the association between duration of tracheal ventilation (TV) and exposure to opioids, sedatives-hypnotics, or general anaesthetics in neonates (O-SH-GA). This study is registered with ClinicalTrials.gov, number NCT01694745. FINDINGS From Oct 1, 2012, to June 30, 2013, 6680 neonates were enrolled in 243 NICUs in 18 European countries. Mean gestational age of these neonates was 35.0 weeks (SD 4.6) and birthweight was 2384 g (1007). 2142 (32%) neonates were given TV, 1496 (22%) non-invasive ventilation (NIV), and 3042 (46%) were kept on spontaneous ventilation (SV). 1746 (82%), 266 (18%), and 282 (9%) neonates in the TV, NIV, and SV groups, respectively, were given sedation or analgesia as a continuous infusion, intermittent doses, or both (p<0.0001). In the participating NICUs, the median use of sedation or analgesia was 89.3% (70.0-100) for neonates in the TV group. Opioids were given to 1764 (26%) of 6680 neonates and to 1589 (74%) of 2142 neonates in the TV group. Midazolam was given to 576 (9%) of 6680 neonates and 536 (25%) neonates of 2142 neonates in the TV group. 542 (25%) neonates in the TV group were given neuromuscular blockers, which were administered as continuous infusions to 146 (7%) of these neonates. Pain assessments were recorded in 1250 (58%) of 2138, 672 (45%) of 1493, and 916 (30%) of 3017 neonates in the TV, NIV, and SV groups, respectively (p<0.0001). In the univariate analysis, neonates given O-SH-GA in the TV group needed a longer duration of TV than did those who were not given O-SH-GA (mean 136.2 h [SD 173.1] vs 39.8 h [94.7] h; p<0.0001). Multivariable and propensity score analyses confirmed this association (p<0.0001). INTERPRETATION Wide variations in sedation and analgesia practices occur between NICUs and countries. Widespread use of O-SH-GA in intubated neonates might prolong their need for mechanical ventilation, but further research is needed to investigate the therapeutic and adverse effects of O-SH-GA in neonates, and to develop new and safe approaches for sedation and analgesia. FUNDING European Communitys Seventh Framework Programme.

Neurodevelopmental outcome after a single course of antenatal steroids in children born preterm: A systematic review and meta-analysis

OBJECTIVE: To systematically review and integrate data on the neurodevelopmental outcome of children after administration of a single course of antenatal corticosteroids for threatened preterm labor. DATA SOURCES: MEDLINE, Scopus, CENTRAL, and www.clinicaltrials.gov (inception to August 2014) using combinations of the terms “prenatal,” “antenatal,” “cortico*,” “*steroid*,” “betamethasone,” “dexamethasone,” “neurodevelopment*,” “*development*,” and “follow-up.” We perused the references of the retrieved articles. METHODS OF STUDY SELECTION: We included randomized and nonrandomized trials reporting on the neurodevelopmental outcomes of children whose mothers were administered a single course of betamethasone or dexamethasone antenatally for threatened preterm birth as opposed to placebo or no treatment. TABULATION, INTEGRATION, AND RESULTS: Summary risk ratio (RR) was calculated for dichotomous data; standardized mean difference was calculated for trials that measured the same outcome but used different methods. Heterogeneity was assessed using the I2 statistic. Sensitivity and subgroup analyses were planned according to study design, specific steroid, and mean gestational age at birth. A single course of antenatal corticosteroids was associated with reduced risk for cerebral palsy (seven studies; treated: 390 of 5,199, untreated: 146 of 1,379; RR 0.678, 95% confidence interval [CI] 0.564–0.815), psychomotor development index less than 70 (two studies; treated: 783 of 3,049, untreated: 258 of 969; RR 0.829, 95% CI 0.737–0.933), and severe disability (five studies; treated: 1,567 of 4,840, untreated: 475 of 1,211; RR 0.787, 95% CI 0.729–0.850). Steroid treatment increased the rates of intact survival (six studies; treated: 1,082 of 2,013, untreated: 273 of 561; RR 1.186, 95% CI 1.056–1.332). Betamethasone was found to significantly decrease the risk for severe disability and increase the rate of intact survival. Dexamethasone increased the rate of intact survival; however, data for dexametasone and the other planned subgroup analyses were limited (fewer than 1,000 children at most). The major limitations involved inclusion of nonrandomized studies and scarcity of data on finer neurodevelopmental outcomes. CONCLUSION: A single course of antenatal corticosteroids in women at high risk for preterm birth appears to improve most neurodevelopmental outcomes in offspring born before 34 weeks of gestation.

Use of ciprofloxacin in neonatal sepsis: lack of adverse effects up to one year.

Aim. To investigate the adverse effects of ciprofloxacin administered to neonates with sepsis on the hematologic indices, the hepatic and renal function and the joints and growth at 1 year follow-up. Methods. In this observational prospective study, 2 groups of septic neonates were studied, 116 neonates who received ciprofloxacin and 100 neonates matched for gestational age and birth weight who did not receive ciprofloxacin. In all neonates the leukocyte and platelet counts as well as the serum concentrations of transaminases, bilirubin, albumin, urea and creatinine were measured before initiation of treatment and on the 10th and 15th to 20th days after treatment initiation. In 77 and 83 infants of the ciprofloxacin and control groups, respectively, the growth at the end of the first year of life was evaluated. Results. No significant differences between the two groups were found in the hematologic and biochemical indices as well as growth at the end of the first year of life. Also no clinical evidence of arthropathy was observed. Conclusions. Treatment of neonatal sepsis with ciprofloxacin resulted in no short term hematologic, renal or hepatic adverse effects and did not appear to be associated with clinical arthropathy or growth impairment at 1 year follow-up evaluation.

Flow cytometric measurement of HLA-DR expression on circulating monocytes in healthy and sick neonates using monocyte negative selection

The aim of this study was to investigate the effect of prematurity, neonatal sepsis, respiratory distress syndrome (RDS) and perinatal asphyxia on monocyte HLA‐DR expression of neonates using a flow cytometric method based on monocyte negative selection. The subjects were one hundred and thirty‐one neonates (59 healthy, 44 septicaemic, 20 with RDS and eight with perinatal asphyxia) and 20 healthy adults. Monocyte HLA‐DR expression was measured using one‐colour HLA‐DR labelling in a gate for monocytes obtained using the combination of CD3‐CD19–PE/CD15–FITC MoAbs. In addition, the common dual staining method using MoAbs against two CD14 epitopes (TUK4, MO2) was evaluated. With the one‐colour HLA‐DR labelling higher purity and recovery values of monocytes were achieved than with the dual labelling method. Healthy neonates had significantly lower percentages of HLA‐DR+ monocytes than adults (69 ± 13% versus 91·5 ± 2·5%) and comparable mean fluorescence intensity (MFI) (119 ± 25 versus 131 ± 26). Values did not differ significantly between healthy term and preterm neonates. Preterm neonates with RDS had a significantly lower percentage of HLA‐DR+ monocytes than the healthy preterm neonates. In neonates with asphyxia both parameters were comparable to those of the healthy ones. Septicaemic neonates presented significantly lower values of both parameters than the healthy, RDS and asphyxiated neonates. Monocyte negative selection provides a reliable estimation of HLA‐DR expression on monocytes. Expression of monocyte HLA‐DR is lower in healthy neonates in comparison with adults and is further decreased in neonates with sepsis and RDS, but it is not influenced by prematurity and perinatal asphyxia.

Non-steroid anti-inflammatory drugs in the treatment of patent ductus arteriosus in European newborns

Introduction. Patent ductus arteriosus (PDA) is a common cause of morbidity and mortality among very low birth weight infants and must be treated on an individual basis. Non-steroid anti-inflammatory drugs (NSAIDs) have been used in the treatment of PDA. However, no general guidelines have been followed. Aim. To know the European reality on NSAIDs in the treatment of PDA in preterm newborns. Methods. A questionnaire was sent to 24 European Societies of Neonatology and Perinatology to be filled, at least, by two neonatal intensive care units (NICUs) in each country, and to three representatives NICUs in Europe. Results. We received 45 filled forms from 19 countries: 1 (2%) from North, 12 (27%) from East, 6 (13%) from West, and 26 (58%) from South Europe. Intravenous (iv) indomethacin is used in 32 (71%) NICUs (88% use a 30–60 min perfusion), iv ibuprofen in 16 (36%), and oral ibuprofen in 13 (29%). In 45% of NICUs a second course is used; 27% prescribed a third one. Prolonged treatment, 4–6 days, is mentioned by 45% of NICUs, in extremely low birth eight infants and after the failure of 3 courses of treatment. Prophylactic treatment is used in two NICUs, 24% treat no hemodynamically significant PDA, 96% treat with NSAIDs hemodynamically significant PDA and one NICU uses surgical closure as first line treatment. The ibuprofen/indomethacin contra-indications and preferences are similar to the literature. Pedea® is the iv ibuprofen solution used and oral ibuprofen is a solution with 20 mg/ml. The choices are influenced by economical reasons in 22% of NICUs. Conclusion. Our data show a wide variation among NICUs and countries, regarding the use of NSAIDs to treat PDA, and that no general guidelines are followed. Guidelines or recommendations are necessary to standardize treatment of PDA in Europe, in order to give to all newborns identical health care opportunities.

Early abnormal amplitude-integrated electroencephalography (aEEG) is associated with adverse short-term outcome in premature infants.

BACKGROUND In preterm infants with IVH the electrocortical background activity is affected and there is a correlation between the severity of cerebral injury to the degree of depression, however the usefulness of the early aEEG recordings has hardly been determined. AIM To identify early aEEG features that could be used as prognostic markers for severe brain injury in prematures. METHODS In 115 infants, 25-32 wk GA, aEEG recordings during the first 72 h of life were correlated with head ultrasound findings. Continuity (Co), sleep-wake cycling (Cy) and amplitude of the lower border (LB) of the aEEG were evaluated by semi-quantitative analysis. RESULTS The infants were divided into four groups based on head ultrasound findings: A (n=72, normal), B [n=16, grades 1-2 intraventricular hemorrhage (IVH)], C (n=21, grades 3-4 IVH) and D (n=6, periventricular leukomalacia). 18 infants (16 of group C and 2 of group D) died during hospitalization. Significantly lower values of all aEEG features were found in group C infants. The presence of pathological tracings (burst-suppression, continuous low-voltage, flat trace) or discontinuous low-voltage (DLV), the absence of Cy and LB<3 μV in the initial aEEG displayed a sensitivity of 88.9%, 63% and 51.9% respectively, for severe brain injury. Logistic regression of aEEG features and GA to the presence or absence of severe injury revealed that only Co was significantly correlated to outcome. Using this feature 83.19% of cases were correctly classified. CONCLUSION Pathological tracings or DLV in the initial aEEG is predictive for poor short-term outcome in premature neonates.

Assessment of continuous pain in newborns admitted to NICUs in 18 European countries

Continuous pain occurs routinely, even after invasive procedures, or inflammation and surgery, but clinical practices associated with assessments of continuous pain remain unknown.