Rolf Schlösser

A prospective, randomized, multicenter trial of high-frequency oscillatory ventilation compared with conventional ventilation in preterm infants with respiratory distress syndrome receiving surfactant

OBJECTIVES To compare high-frequency oscillatory ventilation (HFOV) and intermittent positive pressure ventilation (IPPV) as a primary ventilation mode in preterm infants with respiratory distress syndrome. Primary end points were survival and maintenance of the randomized ventilation mode. STUDY DESIGN Prospective, multicenter, randomized clinical trial. SETTING Level III neonatal intensive care units at three university childrens hospitals. PATIENTS Ninety-six premature infants (gestational age < 32 weeks) randomly assigned to HFOV or IPPV within the first 2 hours of life. All patients received a natural surfactant. No differences were found between the study groups with respect to the demographic data or the severity of respiratory distress syndrome. Infants were stratified at randomization, by birth weight, into two groups: 750 to 1000 gm (n = 32) and 1001 to 1500 gm (n = 64). The centers involved complied with a study protocol that planned a reduction in respiratory pressures when the infants oxygen requirement had reached a fractional concentration of inspired oxygen of 0.6. RESULTS Five patients in the HFOV group died, and eight patients did not respond to the randomized ventilation mode; whereas four patients in the IPPV group died, and nine were switched to HFOV. No differences were found in gas exchange or ventilator support over the first 72 hours. Premature infants with a birth weight < 1000 gm had a significantly shorter course to reach fractional concentration of inspired oxygen of 0.21 while receiving IPPV than those receiving HFOV (9.3+/-4.5 days vs 27.5+/-10.2 days, p = 0.01). No differences were found between the groups in extraalveolar air (HFOV seven; IPPV, seven) and intracranial bleeding (HFOV, nine; IPPV, eight). CONCLUSION After surfactant treatment, HFOV, as a primary ventilation mode in premature infants with respiratory distress syndrome, is as safe and efficacious as conventional ventilation.

Necrotizing enterocolitis of the neonate with Clostridium perfringens: diagnosis, clinical course, and role of alpha toxin

The severity of the clinical course in necrotizing enterocolitis (NEC) associated with Clostridium perfringens (Cp) may support the hypothesis of a specific disease. We conducted a case control study of infants diagnosed with NEC, who underwent surgical treatment over a 7-year period. Patient histories examined characteristics of the infants, bacterial infection as well as NEC’s severity, antibiotic treatment, and clinical course. Infants infected with NEC associated with Cp were compared with NEC patients without Cp. The alpha toxin from Cp type A was detected in most of the isolated strains. Cp was identified as a causative agent of NEC in nine cases. As compared with the control group (n = 32), the onset of disease was earlier in life, the clinical course more severe, and patients had a larger extent of gangrene. Portal venous gas was evident in 77% of all Cp cases, as compared to 25% in the control group. The mortality rate was 44% in the Cp group, and only 18.7% in the control group. Type A Clostridium perfringens was identified in six cases. In each isolate alpha toxin production was proven, but without any correlation to the severity of the clinical course, the extent of intestinal gangrene or mortality. In premature infants NEC in conjunction with Cp seems to be more severe than other NEC cases; it also entails higher mortality and morbidity. Alpha toxin concentrations do not correlate with the severity of the disease. Portal venous gas is highly suggestive for the diagnosis of Cp infection.

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.

Comparison of Effects of Perflubron and Surfactant Lung Lavage on Pulmonary Gas Exchange in a Piglet Model of Meconium Aspiration

In a piglet model of meconium aspiration we compared lavage with surfactant with that with perflubron (PFOB) and a control group. A human meconium suspension was instilled into piglets which were randomized in 3 (n = 6 each) groups. After lung injury, the control group was ventilated with high-frequency oscillatory ventilation (HFOV) without suctioning and lavage. A second group was lavaged with 10 ml/kg diluted surfactant, a third with 10 ml/kg pre-oxygenated PFOB. Thereafter, the animals of both groups were ventilated with HFOV. After lung injury by instillation of meconium, no further improvement in oxygenation was possible in animals of the control group and 3 piglets died during the ventilation. The subjects of the surfactant group improved promptly, and at the end of the study the arterial pO2 was significantly better than immediately after injury as compared with the other groups. Lavage with PFOB had intermediate effects in gas exchange and oxygenation compared to surfactant lavage. No differences were observed in arterial blood pressure and heart rate as well as in histological lung injury score between all groups. Lavage with exogenous surfactant as well as with PFOB improve pulmonary gas exchange in a piglet model of meconium aspiration.

Delayed interval delivery in twin and triplet pregnancies: 6 years of experience in one perinatal center.

Abstract Objective: This study aimed to know the outcome of delayed-interval delivery for twin and triplet pregnancies at 22+0 to 25+0 weeks of gestation. Study design: A retrospective cohort of twin and triplet deliveries at the 23rd to 26th weeks of gestation were managed with delayed interval delivery from 2005 to 2011. Results: From 2005 until 2011, delayed delivery in five twin pregnancies and two triplet pregnancies were performed. The interval between delivery of the first fetus and the remaining twin/triplets was 1–18 days (mean, 9.7 days). In all cases, the first fetus was born vaginally. Survival of the first twin/triplet was 14.3%, whereas 57.1% of the second born twin/triplets survived. Birth weight gained due to delayed delivery was 131 g on average. No severe maternal complications were observed. When compared with a gestation age-matched group, where the delay was not possible, the delayed twin/triplet had a higher survival rate (57.1% vs. 0%, P=0.05). Conclusion: In multiple pregnancies with preterm delivery between completed 22 and completed 25 weeks of gestational age, delayed delivery seems to be a useful therapeutic option to achieve a better outcome of the remaining fetus or fetuses.

Neurodevelopmental outcomes of extremely low birthweight infants randomised to different PCO2 targets: the PHELBI follow-up study

Background Tolerating higher partial pressures of carbon dioxide (PCO2) in mechanically ventilated extremely low birthweight infants to reduce ventilator-induced lung injury may have long-term neurodevelopmental side effects. This study analyses the results of neurodevelopmental follow-up of infants enrolled in a randomised multicentre trial. Methods Infants (n=359) between 400 and 1000 g birth weight and 23 0/7–28 6/7 weeks gestational age who required endotracheal intubation and mechanical ventilation within 24 hours of birth were randomly assigned to high PCO2 or to a control group with mildly elevated PCO2 targets. Neurodevelopmental follow-up examinations were available for 85% of enrolled infants using the Bayley Scales of Infant Development II, the Gross Motor Function Classification System (GMFCS) and the Child Development Inventory (CDI). Results There were no differences in body weight, length and head circumference between the two PCO2 target groups. Median Mental Developmental Index (MDI) values were 82 (60–96, high target) and 84 (58–96, p=0.79). Psychomotor Developmental Index (PDI) values were 84 (57–100) and 84 (65–96, p=0.73), respectively. Moreover, there was no difference in the number of infants with MDI or PDI <70 or <85 and the number of infants with a combined outcome of death or MDI<70 and death or PDI<70. No differences were found between results for GMFCS and CDI. The risk factors for MDI<70 or PDI<70 were intracranial haemorrhage, bronchopulmonary dysplasia, periventricular leukomalacia, necrotising enterocolitis and hydrocortisone treatment. Conclusions A higher PCO2 target did not influence neurodevelopmental outcomes in mechanically ventilated extremely preterm infants. Adjusting PCO2 targets to optimise short-term outcomes is a safe option. Trial registration number ISRCTN56143743.

Follow-Up of Children with Gastrointestinal Malformations and Postnatal Surgery and Anesthesia: Evaluation at Two Years of Age

Background: The impact of general anesthesia is considered a risk factor for developmental delay. Very few studies have been performed to measure the neurodevelopmental outcome of patients with selected malformations. Objectives: The purpose of this ambidirectional cohort study was to measure the neurodevelopmental outcome of patients with congenital gastrointestinal-tract malformations (GIM). Methods: Forty patients with relevant congenital GIM born in the period from June 2008 to April 2011 were identified. The inclusion criteria were a gestational age >32 completed weeks and surgery that required a general anesthetic within the first 28 days of life. The neonatal characteristics and anesthesia data were retrospectively collected. Based on information about the neonatal characteristics and socioeconomic background, a matched pair was found. All participants were tested at the corrected age of 24 months with the Bayley Scales of Infant Development II assessment. Results: The outcome was split into the psychomotor index (PDI) and mental developmental index (MDI). The patient group achieved a mean PDI of 103 and the control group achieved 106, i.e. these values were not significantly different. The mean MDI was 102 in the patient group and 110 in the control group. This difference was significant (p = 0.022). Detailed analysis of the items showed no significance for nonverbal items but a significant difference for verbal items (p = 0.029). Further analysis showed no correlation between relevant anesthesia data and the neurodevelopmental outcome. Conclusions: We found lower MDI scores due to worse verbal abilities in the patient group. Children born with GIM should be considered a risk group with respect to language development.

Influence of PCO2 Control on Clinical and Neurodevelopmental Outcomes of Extremely Low Birth Weight Infants

Background: Levels or fluctuations in the partial pressure of CO2 (PCO2) may affect outcomes for extremely low birth weight infants. Objectives: In an exploratory analysis of a randomized trial, we hypothesized that the PCO2 values achieved could be related to significant outcomes. Methods: On each treatment day, infants were divided into 4 groups: relative hypocapnia, normocapnia, hypercapnia, or fluctuating PCO2. Ultimate assignment to a group for the purpose of this analysis was made according to the group in which an infant spent the most days. Statistical analyses were performed with analysis of variance (ANOVA), the Kruskal-Wallis test, the χ2 test, and the Fisher exact test as well as by multiple logistic regression. Results: Of the 359 infants, 57 were classified as hypocapnic, 230 as normocapnic, 70 as hypercapnic, and 2 as fluctuating PCO2. Hypercapnic infants had a higher average product of mean airway pressure and fraction of inspired oxygen (MAP × FiO2). For this group, mortality was higher, as was the likelihood of having moderate/severe bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and poorer neurodevelopment. Multiple logistic regression analyses showed an increased risk for BPD or death associated with birth weight (p < 0.001) and MAP × FiO2 (p < 0.01). The incidence of adverse neurodevelopment was associated with birth weight (p < 0.001) and intraventricular hemorrhage (IVH; p < 0.01). Conclusions: Birth weight and respiratory morbidity, as measured by MAP × FiO2, were the most predictive of death or BPD and NEC, whereas poor neurodevelopmental outcome was associated with low birth weight and IVH. Univariate models also identified PCO2. Thus, hypercapnia seems to reflect greater disease severity, a likely contributor to differences in outcomes.

An open-label, randomized efficacy and safety trial of subcutaneous and intramuscular BT088 (Fovepta) human hepatitis B immunoglobulin in neonates of HBV-carrier mothers

Abstract Objective: The objective of the study was to assess the efficacy and safety of subcutaneously (SC) and intramuscularly (IM) administered BT088 (Fovepta) human hepatitis B immunoglobulin in neonates of hepatitis B surface antigen (HBs/HBsAg)-positive mothers in the prevention of hepatitis B infection. Methods: This was an open, prospective, multicenter trial, in which infants were randomized to receive a single SC or IM dose of BT088 (200 IU, 0.4 mL) within 12 h of birth simultaneously with active vaccination against hepatitis B. The primary efficacy variable was the response rate, defined as the proportion of infants whose anti-HBs concentration was negative at predose and ≥100 IU/L 48 to 72 h postdose. Results: The full analysis set included 31 neonates (17 SC and 14 IM). Response was experienced by 30 (96.8%) of 31 infants who received BT088 by either route of administration. The median postdose anti-HBs concentration was 261.2 IU/L. One neonate had a postdose anti-HBs level lower than 100 IU/L (81.0 IU/L). No infant experienced seroconversion during the 7- to 15-month follow-up. BT088 was well tolerated, with no allergic-like, or injection-site reactions observed. Conclusion: SC and IM administration of 200 IU (0.4 mL) BT088 resulted in protective serum anti-HBs titers within 72 h of administration in newborn infants and was well tolerated and effective.