C. Gebauer

Hemodynamics among neonates with hypoxic-ischemic encephalopathy during whole-body hypothermia and passive rewarming.

OBJECTIVE. To assess changes in cardiac performance, with Doppler echocardiography, among newborns with hypoxic-ischemic encephalopathy during mild therapeutic hypothermia and during rewarming. METHODS. For 7 asphyxiated neonates (birth weight: 1840–3850 g; umbilical artery pH: 6.70–6.95) who received mild whole-body hypothermia, the following hemodynamic parameters were determined immediately before rewarming (33°C) and during passive rewarming (35°C and 37°C): heart rate, systolic and diastolic blood pressure, core and peripheral temperatures, left ventricular ejection time, mean velocity of aortic flow, stroke volume, and cardiac output. RESULTS. Heart rate decreased during hypothermia. Bradycardia, with heart rates below 80 beats per minute, did not occur. The median difference between core and peripheral temperatures decreased from 2.0°C (range: 0–6.2°C) during hypothermia to 0.7°C (range: 0.4–1.9°C) at normothermia. Cardiac output was reduced to 67% and stroke volume to 77% of the posthypothermic level. The median heart rate was 129 beats per minute before rewarming and increased to 148 beats per minute during complete rewarming. Before and during passive rewarming, hypotension was not observed. Before, during, and at the end of rewarming, the following parameters increased: mean velocity of aortic flow (median: 44, 55, and 58 cm/second, respectively), stroke volume (median: 1.42, 1.55, and 1.94 mL/kg, respectively), and cardiac output (median: 169, 216, and 254 mL/kg per minute, respectively). Left ventricular ejection time remained unchanged. CONCLUSIONS. Whole-body hypothermia resulted in reduced cardiac output, which reached normal levels at the end of passive rewarming, at normothermia. Physiologic cardiovascular mechanisms seemed to be intact to provide sufficient tissue perfusion, with normal blood lactate levels.

Leptin in maternal serum and breast milk: association with infants' body weight gain in a longitudinal study over 6 months of lactation.

The adipokine leptin has been detected in human breast milk, but its effect on postnatal growth and development remains largely unclear. We hypothesized that leptin could affect infants body weight gain during early lactation in the first 6 mo of life. Therefore, we evaluated leptin levels in maternal serum and breast milk of 23 healthy, lactating mothers and their neonates in a prospective, longitudinal study. Leptin concentration was quantified by a commercially available human leptin RIA. Our results showed that leptin levels in breast milk were 22-fold lower than in maternal serum, but both parameters were positively correlated to each other (r = 0.431, p = 0.001) and to maternal BMI (serum: r = 0.512, p < 0.001; milk: r = 0.298, p < 0.001) over 6 mo of lactation. A negative association was found between breast milk leptin levels during the first week after delivery and the infant weight gain from the end of the first to the sixth month (r = −0.681, p = 0.007). This suggests that milk-borne leptin provides a link between maternal body composition and infant growth and development and plays a critical role in regulating appetite and food intake during early infancy.

Continuous Infusion of Clonidine in Ventilated Newborns and Infants: A Randomized Controlled Trial

Objectives: To assess the influence of an infusion of clonidine 1 &mgr;g/kg/hr on fentanyl and midazolam requirement in ventilated newborns and infants. Design: Prospective, double-blind, randomized controlled multicenter trial. Controlled trials.com/ISRCTN77772144. Setting: Twenty-eight level 3 German PICUs/neonatal ICUs. Patients: Ventilated newborns and infants: stratum I (1–28 d), stratum II, (29–120 d), and stratum III (121 d to 2 yr). Interventions: Patients received clonidine 1 &mgr;g/kg/hr or placebo on day 4 after intubation. Fentanyl and midazolam were adjusted to achieve a defined level of analgesia and sedation according to Hartwig score. Measurements and Main Results: Two hundred nineteen infants were randomized; 212 received study medication, 69.7% were ventilated in the postoperative care and 30.3% for other reasons. Primary endpoint: consumption of fentanyl and midazolam in the 72 hours following the onset of study medication (main observation period) in the overall study population. The confirmatory analysis of the overall population showed no difference in the consumption of fentanyl and midazolam. Explorative age-stratified analysis demonstrated that in stratum I (n = 112) the clonidine group had a significantly lower consumption of fentanyl (clonidine: 2.1 ± 1.8 &mgr;g/kg/hr, placebo: 3.2 ± 3.1 &mgr;g/kg/hr; p = 0.032) and midazolam (clonidine: 113.0 ± 100.1 &mgr;g/kg/hr, placebo: 180.2 ± 204.0 &mgr;g/kg/hr; p = 0.030). Strata II (n = 43) and III (n = 46) showed no statistical difference. Sedation and withdrawal-scores were significantly lower in the clonidine group of stratum I (p < 0.001). Frequency of severe adverse events did not differ between groups. Conclusions: Clonidine 1 &mgr;g/kg/hr in ventilated newborns reduced fentanyl and midazolam demand with deeper levels of analgesia and sedation without substantial side effects. This was not demonstrated in older infants, possibly due to lower clonidine serum levels.

Permissive hypercapnia in extremely low birthweight infants (PHELBI): a randomised controlled multicentre trial

BACKGROUND Tolerating higher partial pressure of carbon dioxide (pCO2) in mechanically ventilated, extremely low birthweight infants might reduce ventilator-induced lung injury and bronchopulmonary dysplasia. We aimed to test the hypothesis that higher target ranges for pCO2 decrease the rate of bronchopulmonary dysplasia or death. METHODS In this randomised multicentre trial, we recruited infants from 16 tertiary care perinatal centres in Germany with birthweight between 400 g and 1000 g and gestational age 23-28 weeks plus 6 days, who needed endotracheal intubation and mechanical ventilation within 24 h of birth. Infants were randomly assigned to either a high target or control group. The high target group aimed at pCO2 values of 55-65 mm Hg on postnatal days 1-3, 60-70 mm Hg on days 4-6, and 65-75 mm Hg on days 7-14, and the control target at pCO2 40-50 mmHg on days 1-3, 45-55 mm Hg on days 4-6, and 50-60 mm Hg on days 7-14. The primary outcome was death or moderate to severe bronchopulmonary dysplasia, defined as need for mechanical pressure support or supplemental oxygen at 36 weeks postmenstrual age. Cranial ultrasonograms were assessed centrally by a masked paediatric radiologist. This trial is registered with the ISRCTN registry, number ISRCTN56143743. RESULTS Between March 1, 2008, and July 31, 2012, we recruited 362 patients of whom three dropped out, leaving 179 patients in the high target and 180 in the control group. The trial was stopped after an interim analysis (n=359). The rate of bronchopulmonary dysplasia or death in the high target group (65/179 [36%]) did not differ significantly from the control group (54/180 [30%]; p=0·18). Mortality was 25 (14%) in the high target group and 19 (11%; p=0·32) in the control group, grade 3-4 intraventricular haemorrhage was 26 (15%) and 21 (12%; p=0·30), and the rate of severe retinopathy recorded was 20 (11%) and 26 (14%; p=0·36). INTERPRETATION Targeting a higher pCO2 did not decrease the rate of bronchopulmonary dysplasia or death in ventilated preterm infants. The rates of mortality, intraventricular haemorrhage, and retinopathy did not differ between groups. These results suggest that higher pCO2 targets than in the slightly hypercapnic control group do not confer increased benefits such as lung protection. FUNDING Deutsche Forschungsgemeinschaft.

Does the enteral feeding advancement affect short-term outcomes in very low birth weight infants?

Background and Objectives: Controversy exists regarding the optimal enteral feeding regimen of very low birth weight infants (VLBW). Rapid advancement of enteral feeding has been associated with an increased rate of necrotizing enterocolitis. In contrast, delaying enteral feeding may have unfavorable effects on nutrition, growth, and neurodevelopment. The aim is to compare the short-term outcomes of VLBW infants in tertiary care centers according to their enteral feeding advancement. Patients and Methods: We prospectively studied the influence of center-specific enteral feeding advancement in 1430 VLBW infants recruited from 13 tertiary neonatal intensive care units in Germany on short-term outcome parameters. The centers were post hoc stratified to “rapid advancement to full enteral feeds” (median duration of advancement to full enteral feeds ≤12.5 days; 6 centers), that is, rapid advancement (RA), or “slow advancement to full enteral feeds” (median duration of advancement to full enteral feeds >12.5 days; 7 centers), that is, slow advancement (SA). Results: VLBW infants born in centers with SA (n = 713) had a significantly higher rate of sepsis compared with VLBW infants born in centers with RA (n = 717), which was particularly evident for late-onset sepsis (14.0% vs 20.4%; P = 0.002). Furthermore, more central venous lines (48.6% vs 31.1%, P < 0.001) and antibiotics (92.4% vs 77.7%, P < 0.001) were used in centers with SA. Conclusions: Center differences in enteral feeding advancement occur and may have a significant impact on short-term outcomes such as nosocomial sepsis. Large, multicenter, prospective trials are required to further elucidate the optimal feeding strategy for VLBW infants.

The effect of maturation and sedation on amplitude‐integrated electroencephalogram of the preterm neonate: Results of a prospective study

Background and aim: Amplitude‐integrated electroencephalogram (aEEG) is becoming more common in NICUs for monitoring infants after perinatal asphyxia. We used aEEGs for preterm infants, and analysed the influence of sedation and maturation on their aEEG, focusing on continuous activity. Methods: Weekly or biweekly aEEGs were performed in preterm infants and evaluated by visual analysis. Results: We analysed 92 aEEGs of 56 preterm infants (gestational age (GA) 24 + 6 to 34 + 0 wk, median 30 + 0 wk). In their first week of life, children with higher GA had a higher percentage of continuous activity: with a GA ≤ 28 + 0 wk it was 8.1%, 33.5% with a GA from 28 + 1 to 30 + 0 wk (p= 0.02), 85.9% with a GA from 30 + 1 to 32 + 0 wk (p= 0.005), and 89.1% with a GA from 32 + 1 to 34 + 0 wk. Continuous activity increased with growing postnatal age. With a GA ≤ 28 + 0 wk, it rose from 8.1% (first week) to 55.3% (second week) and reached 96.8% (week 6/7) (p= 0.017). With GA from 28 + 1 to 30 + 0 wk, continuous activity was 33.5% (first week) and 86.6% (second week) (p= 0.03).

Higher Rate of Cord-Related Adverse Events in Neonates with Dry Umbilical Cord Care Compared to Chlorhexidine Powder

Objective: Best practice for umbilical cord care (UC) still remains controversial in developed countries with aseptic perinatal care. A bicenter randomized clinical trial was performed to evaluate the efficacy of chlorhexidine (CX) powder versus dry cord care (DC) for UC. Patients and Methods: All neonates of two neonatal care units were invited to take part in the study. Participants were randomized to either DC or UC with CX powder (0.1%). Primary study outcome was the cord separation time. Secondary outcomes were omphalitis, granuloma of the umbilical ground, adverse events and parents’ treatment satisfaction. The outcome parameters were documented at a hospital-located study visit 10–14 days after birth. Results: 669 neonates were enrolled in the trial. 337 were randomized to receive CX powder for umbilical cord care, 332 to DC. Cord separation time was 7.0 ± 2.5 days in CX-treated neonates and 7.8 ± 2.9 days in DC (p < 0.001). There were 9 cases of omphalitis, 2 in the CX group, 7 in the DC group (p = 0.1). No difference in the occurrence of umbilical granuloma between the treatment regimens was detected. Neonates randomized to CX were less likely to have an adverse event (140 in 109 subjects vs. 205 in 149 subjects in the DC neonates; p = 0.001). Half of these adverse events were cord-related. Neonates randomized to DC had nearly twice as many cord-related adverse events as those with CX treatment (CX: 58 in 54 patients vs. DC: 110 in 97 patients; p < 0.001). Parents’ treatment satisfaction was significantly higher in the neonates with CX cord care. Conclusions: Cord-related adverse events in neonatal umbilical cord care remain a clinical issue. Even in an aseptic birth context in a developed country, cord care with CX powder showed a reduction of cord-related adverse events.

Epidemic Microclusters of Blood-Culture Proven Sepsis in Very-Low-Birth Weight Infants: Experience of the German Neonatal Network

Introduction We evaluated blood culture-proven sepsis episodes occurring in microclusters in very-low-birth-weight infants born in the German Neonatal Network (GNN) during 2009–2010. Methods Thirty-seven centers participated in GNN; 23 centers enrolled ≥50 VLBW infants in the study period. Data quality was approved by on-site monitoring. Microclusters of sepsis were defined as occurrence of at least two blood-culture proven sepsis events in different patients of one center within 3 months with the same bacterial species. For microcluster analysis, we selected sepsis episodes with typically cross-transmitted bacteria of high clinical significance including gram-negative rods and Enterococcus spp. Results In our cohort, 12/2110 (0.6%) infants were documented with an early-onset sepsis and 235 late-onset sepsis episodes (≥72 h of age) occurred in 203/2110 (9.6%) VLBW infants. In 182/235 (77.4%) late-onset sepsis episodes gram-positive bacteria were documented, while coagulase negative staphylococci were found to be the most predominant pathogens (48.5%, 95%CI: 42.01–55.01). Candida spp. and gram-negative bacilli caused 10/235 (4.3%, 95%CI: 1.68% –6.83%) and 43/235 (18.5%) late-onset sepsis episodes, respectively. Eleven microclusters of blood-culture proven sepsis were detected in 7 hospitals involving a total 26 infants. 16/26 cluster patients suffered from Klebsiella spp. sepsis. The median time interval between the first patient’s Klebsiella spp. sepsis and cluster cases was 14.1 days (interquartile range: 1–27 days). First patients in the cluster, their linked cases and sporadic sepsis events did not show significant differences in short term outcome parameters. Discussion Microclusters of infection are an important phenomenon for late-onset sepsis. Most gram-negative cluster infections occur within 30 days after the first patient was diagnosed and Klebsiella spp. play a major role. It is essential to monitor epidemic microclusters of sepsis in surveillance networks to adapt clinical practice, inform policy and further improve quality of care.

Polymorphisms in the Renin-Angiotensin System and Outcome of Very-Low-Birthweight Infants

Background: The insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE-ins/del) and the angiotensin II type 1 receptor 1166A/C polymorphism (ATR1166A/C) were reported to be associated with several unfavorable outcome parameters in preterm infants like bronchopulmonary dysplasia, persistent ductus arteriosus and impaired insulin sensitivity. Objective: To confirm the above-mentioned associations in a large cohort of very-low-birthweight (VLBW) infants. Method: Clinical data of VLBW infants were prospectively recorded. The ACE-ins/del polymorphism and the ATR1166A/C polymorphism were determined by polymerase chain reaction in 1,209 and 1,168 infants, respectively. Results: There was no significant association between ACE-ins/del or ATR1166A/C genotype and outcome parameters (death, intraventricular hemorrhage, sepsis, bronchopulmonary dysplasia, ventilation, supplemental oxygen at discharge, postnatal treatment with insulin, surgery for intestinal perforation/necrotizing enterocolitis/retinopathy of prematurity/persistent ductus arteriosus. Conclusion: Both known functional polymorphisms of the renin-angiotensin system do not seem to be associated with the outcome of VLBW infants.

Influence of Smoking and Alcohol during Pregnancy on Outcome of VLBW Infants

BACKGROUND Nicotine and alcohol consumption have been associated with premature delivery and adverse neonatal outcome. We wanted to analyze the influence of self-reported nicotine and alcohol consumption on outcome of VLBW infants. MATERIAL AND METHODS In an ongoing multicenter study 2475 parents of former very low birth weight (VLBW) infants born between January 2009 and December 2011 answered questionnaires about maternal smoking habits and alcohol consumption during pregnancy. 2463 (99.5%) completed questions on alcohol consumption and 2462 (99.5%) on smoking habits. These infants were stratified to reported maternal smoking and alcohol consumption during pregnancy. We compared the reasons for premature delivery, neonatal outcome and parental reports on bronchitis during the first year of life, as well as growth and development at age 2 years to pregnancy exposure. RESULTS In nicotine exposed infants intrauterine growth restriction (31 vs. 21%, p<0.01), a birth weight below the 10th percentile (26 vs. 17%, p<0.01) and placenta abruption (9.2 vs. 5.8%, p<0.05) was seen more often. Premature rupture of membranes (24 vs. 30%, p<0.05) or HELLP syndrome (6 vs. 11%, p<0.01) was less frequent. A birth weight below the 3rd percentile was seen more frequently in mothers with reported alcohol consumption (13 vs. 6%, p<0.05). We noted an increased rate of BPD and ROP if mothers reported smoking during pregnancy (p<0.05). Growth parameters and scores on Bayley Sscales of infant development at age 2 years did not differ. CONCLUSION Smoking during pregnancy results in a high rate of growth restricted VLBW infants. Prenatal exposition to nicotine seems to increase postnatal complications such as BPD und ROP.