Safety and Feasibility of Long-Distance Aeromedical Transport of Neonates and Children in Fixed-Wing Air Ambulance.

In cases of critical injury or illness abroad, fixed-wing air ambulance aircraft is employed to repatriate children to their home country. Air ambulance aircraft also transport children to foreign countries for treatment not locally available and newborns back home that have been born prematurely abroad. In this retrospective observational study, we investigated demographics, feasibility, and safety and outcomes of long-distance and international aeromedical transport of neonates and children. The study included 167 pediatric patients, 56 of those preterm neonates. A total of 41 patients were ventilated, 45 requiring oxygen prior to the transport, 57 transferred from an intensive care unit (ICU), and 48 to an ICU. Patients were transported by using Learjet 31A, Learjet 45, Learjet 55, and Bombardier Challenger 604, with a median transport distance of 1,008 nautical miles (NM), median transport time of 04:45 hours (median flight time = 03:00 hours), flight time ≥8 hours in 15 flights, and transport time ≥8 hours in 29 missions. All transports were accompanied by a pediatric physician/nurse team. An increase in FiO 2 during the transport was documented in 47/167 patients (28%). Therapy escalation (other than increased oxygen) was reported in 18 patients, and technical adverse events in 3 patients. No patient required CPR or died during the transport. Clinical transport outcome was rated by the accompanying physician as unchanged in 163 transports, improved in 4, and deteriorated in none. In summary, international, long-distance transport of neonatal and pediatric patients performed by experienced and well-equipped transport teams is feasible. Neither major adverse events nor physician-rated clinical deteriorations were observed in this group of patients.

The Use of Off-Label Medications in Newborn Infants Despite an Approved Alternative Being Available-Results of a National Survey.

Neonates continue to be treated with off-label or unlicensed drugs while in hospital. However, some medications that have previously been used in adults underwent clinical testing and licensure for use with a different indication in the neonatal and pediatric population. Almost always, the marketing of these newly approved substances in a niche indication is accompanied by a steep increase in the price of the compound. We investigated the use of the approved formulation or the cheaper off-label alternative of Ibuprofen (Pedea®), Propanolol (Hemangiol®) and Caffeine Citrate (Peyona®) in neonatal clinical practice by conducting a National Survey of 214 Perinatal Centers in Germany. We also assessed price differences between on- and off-label alternatives and the extend of the clinical development program of the on-label medication in the neonatal population. On-label medication was more frequently used than the off-label alternative in all indications (PDA: on-label to off-label ratio 1:0.26, Apnea: 1:0.56, Hemangioma 1:0.76). All sponsors did conduct placebo-controlled Phase III trials with efficacy and safety endpoints in the target population and the number of participants in the target population varied between 82 and 497. Costs for the three drugs in their approved and marketed formulations increased in median 405-fold compared with the corresponding off-label alternative. Overall, about one out of three neonatologists prescribed an off-label or non-approved drug to patients despite an alternative medication that is approved for the indication in the target population being available.

Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities.

Necrotizing enterocolitis (NEC) is a severe, currently untreatable intestinal disease that predominantly affects preterm infants and is driven by poorly characterized inflammatory pathways. Here, human and murine NEC intestines exhibit an unexpected predominance of type 3/TH17 polarization. In murine NEC, pro-inflammatory type 3 NKp46-RORγt+Tbet+ innate lymphoid cells (ILC3) are 5-fold increased, whereas ILC1 and protective NKp46+RORγt+ ILC3 are obliterated. Both species exhibit dysregulation of intestinal TLR repertoires, with TLR4 and TLR8 increased, but TLR5-7 and TLR9-12 reduced. Transgenic IL-37 effectively protects mice from intestinal injury and mortality, whilst exogenous IL-37 is only modestly efficacious. Mechanistically, IL-37 favorably modulates immune homeostasis, TLR repertoires and microbial diversity. Moreover, IL-37 and its receptor IL-1R8 are reduced in human NEC epithelia, and IL-37 is lower in blood monocytes from infants with NEC and/or lower birthweight. Our results on NEC pathomechanisms thus implicate type 3 cytokines, TLRs and IL-37 as potential targets for novel NEC therapies.

Early Bacterial Colonization and Antibiotic Resistance Gene Acquisition in Newborns.

Several studies have recently identified the main factors contributing to the bacterial colonization of newborns and the dynamics of the infant microbiome development. However, most of these studies address large time periods of weeks or months after birth, thereby missing on important aspects of the early microbiome maturation, such as the acquisition of antibiotic resistance determinants during postpartum hospitalization. The pioneer bacterial colonization and the extent of its associated antibiotic resistance gene (ARG) dissemination during this early phase of life are largely unknown. Studies addressing resistant bacteria or ARGs in neonates often focus only on the presence of particular bacteria or genes from a specific group of antibiotics. In the present study, we investigated the gut-, the oral-, and the skin-microbiota of neonates within the first 72 h after birth using 16S rDNA sequencing approaches. In addition, we screened the neonates and their mothers for the presence of 20 different ARGs by directed TaqMan qPCR assays. The taxonomic analysis of the newborn samples revealed an important shift of the microbiota during the first 72 h after birth, showing a clear site-specific colonization pattern in this very early time frame. Moreover, we report a substantial acquisition of ARGs during postpartum hospitalization, with a very high incidence of macrolide resistance determinants and mecA detection across different body sites of the newborns. This study highlights the importance of antibiotic resistance determinant dissemination in neonates during hospitalization, and the need to investigate the implication of the mothers and the hospital environment as potential sources of ARGs.

Overcrowding in a neonatal intermediate care unit: impact on the incidence of multidrug-resistant gram-negative organisms.

BACKGROUND: Overcrowding, reduced nurse to patient ratio, limited distance between incubators and absence of microbiological surveillance have been shown to promote spread of multidrug-resistant gram-negative organisms (MDRGN) in patients with birthweight < 1500 g. Patients > 1500 g treated on an intermediate care unit are unrepresented in recent literature. We therefore intended to present data obtained from a short-term overcrowded neonatal intermediate care unit (NIMCU) at a level III (international categorization) perinatal center at University Hospital Frankfurt, Germany. METHODS: During a 25 day overcrowding (OV) and 28 day post-overcrowding period (POST-OV) on NIMCU, epidemiological data obtained from continuously hold microbiological surveillance were investigated and compared to the last 12 months of ward-regular bed occupancy preceding OV (PRAE-OV). RESULTS: During OV, the number of patients simultaneously treated at the NIMCU increased from 18 to 22, resulting in a reduced bed-to-bed space. Nurse: patient ratio was 4:22 during OV compared to 3:18 during PRAE-OV. Cumulative incidence of MDRGN was 4.7% in OV and 2.4% POST-OV compared to 4.8% to PRAE-OV, respectively, without any significant variations. During OV and POST-OV, septic episodes due to MDRGN were not observed. In one case, potential nosocomial transmission of Enterobacter cloacae resistant to Piperacillin and 3rd/4th generation cephalosporins was observed. CONCLUSIONS: Prevention of nosocomial spread of MDRGN in an overcrowded NIMCU is based on staff's diligent training and adequate staffing. Concise microbiological surveillance should be guaranteed to escort through overcrowding periods. In our setting, impact of bed-to-bed distance on MDRGN transmission seemed to be less strong.

Group B streptococcus infections in neonates admitted to a German NICU: Emphasis on screening and adherence to pre-analytical recommendations.

BACKGROUND: Infections by group B streptococci (GBS), e.g. Streptococcus agalactiae, presenting as early-onset disease (EOD) or late-onset disease (LOD), are leading causes of severe infections in newborn and premature patients. Although screening and intra partum antibiotic prophylaxis are frequently performed, vertically transmitted GBS remain a challenge for pediatrics. AIMS: In order to prevent or reduce potential life-threatening events, this study retrospectively investigated epidemiological, microbiological and clinical aspects of infants admitted to the Division of Neonatology at the Department of Pediatrics at the University Hospital Frankfurt, Germany (UHF). STUDY DESIGN AND SUBJECTS: Between January 2010 and January 2016, perinatal GBS screening status, clinical presentation of EOD or LOD and therapeutic management of neonates admitted to UHF were retrospective analysed. Infants tested positive for GBS within their first three months of life were included; patient data were obtained from the chart report. Severity of neonatal disease was analysed by using the NEOMOD and CRIB score. RESULTS: 108 GBS infected infants born to 105 mothers were observed. N=101 of them (93.5%) presented with EOD, whereof n=9 (10%) primarily presented with pneumonia or pneumothorax. In 82 (78%) mothers of infected infants GBS status was unknown prior to hospitalization of the neonate. 3/108 (2.8%) infants died from GBS septicemia. CONCLUSION: Avoidance of GBS transmission sub partu is the key issue in preventing neonatal GBS infection and should be the focus of preventive strategies. Our results highlight the impact of perinatal screening.

Immune cell subsets at birth may help to predict risk of late-onset sepsis and necrotizing enterocolitis in preterm infants.

BACKGROUND: Parameters predicting late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) in preterm infants would be valuable. Ten-color flow-cytometry enables the estimation of cellular immune status requiring only small sample volumes. AIMS: Identifying predictive parameters for LOS and NEC in the cellular immune status of preterm infants. STUDY DESIGN AND SUBJECTS: In this prospective study in 40 preterm infants (week 26+0 to 30+6) and 10 healthy full-term newborn infants (control group, week 37+0 to 40+6), flow cytometric analyses of lymphocyte subpopulations were performed between the 2nd and the 6th day of life, with a follow-up until the preterm infant reached the calculated gestational age of week 40. Patients' episodes of infections and NEC were analyzed according to the NEO-KISS criteria of the German National Reference Center. RESULTS: Ten preterm infants showed events within the first week of life and were excluded from the analysis. Of the other 30, five developed NEC, twelve LOS. In patients with LOS, the proportion of double-negative (DN) T cells was significantly elevated compared to patients without LOS, while immune-regulatory CD56bright and CD56negCD16+ NK cells were significantly decreased (p<0.05). Patients with NEC showed a reduction in the NK cell proportion (<3.7%) and significantly decreased naïve cytotoxic CD45RA+CD62L+ T cells (p<0.05). CONCLUSION: NK cells and DN-T cell counts within the first week of life may be predictors for NEC and LOS in preterm infants. In order to identify patients at risk early, further analysis of these populations might be of interest.

Analysis of Endothelial Adherence of Bartonella henselae and Acinetobacter baumannii Using a Dynamic Human Ex Vivo Infection Model.

Bacterial adherence determines the virulence of many human-pathogenic bacteria. Experimental approaches elucidating this early infection event in greater detail have been performed using mainly methods of cellular microbiology. However, in vitro infections of cell monolayers reflect the in vivo situation only partially, and animal infection models are not available for many human-pathogenic bacteria. Therefore, ex vivo infection of human organs might represent an attractive method to overcome these limitations. We infected whole human umbilical cords ex vivo with Bartonella henselae or Acinetobacter baumannii under dynamic flow conditions mimicking the in vivo infection situation of human endothelium. For this purpose, methods for quantifying endothelium-adherent wild-type and trimeric autotransporter adhesin (TAA)-deficient bacteria were set up. Data revealed that (i) A. baumannii binds in a TAA-dependent manner to endothelial cells, (ii) this organ infection model led to highly reproducible adherence rates, and furthermore, (iii) this model allowed to dissect the biological function of TAAs in the natural course of human infections. These findings indicate that infection models using ex vivo human tissue samples ("organ microbiology") might be a valuable tool in analyzing bacterial pathogenicity with the capacity to replace animal infection models at least partially.

Lack of blinding of outcome assessors in animal model experiments implies risk of observer bias.

OBJECTIVES: To examine the impact of not blinding outcome assessors on estimates of intervention effects in animal experiments modeling human clinical conditions. STUDY DESIGN AND SETTING: We searched PubMed, Biosis, Google Scholar, and HighWire Press and included animal model experiments with both blinded and nonblinded outcome assessors. For each experiment, we calculated the ratio of odds ratios (ROR), that is, the odds ratio (OR) from nonblinded assessments relative to the corresponding OR from blinded assessments. We standardized the ORs according to the experimental hypothesis, such that an ROR <1 indicates that nonblinded assessor exaggerated intervention effect, that is, exaggerated benefit in experiments investigating possible benefit or exaggerated harm in experiments investigating possible harm. We pooled RORs with inverse variance random-effects meta-analysis. RESULTS: We included 10 (2,450 animals) experiments in the main meta-analysis. Outcomes were subjective in most experiments. The pooled ROR was 0.41 (95% confidence interval [CI], 0.20, 0.82; I(2) = 75%; P < 0.001), indicating an average exaggeration of the nonblinded ORs by 59%. The heterogeneity was quantitative and caused by three pesticides experiments with very large observer bias, pooled ROR was 0.20 (95% CI, 0.07, 0.59) in contrast to the pooled ROR in the other seven experiments, 0.82 (95% CI, 0.57, 1.17). CONCLUSION: Lack of blinding of outcome assessors in animal model experiments with subjective outcomes implies a considerable risk of observer bias.

Purpura fulminans after therapeutic hypothermia in an asphyxiated neonate with streptococcemia.

OBJECTIVE: Therapeutic hypothermia is an established therapeutic regimen in severely asphyxiated term neonates. The amount of cerebral injury is reduced resulting in an improved neurologic outcome. Therapeutic hypothermia-induced side effects mostly affect the circulatory system, kidney, and liver. However, asphyxia and hypothermia in itself reduce the hemostatic capacity of each individual organism. STUDY DESIGN: A case of a neonate with severe asphyxia and purpura fulminans after hypothermia is described. RESULTS AND CONCLUSION: Although purpura fulminans cannot be attributed to hypothermia solely, the influence of hypothermia on hemostasis may have promoted severe coagulopathy with a fatal outcome. Further studies are necessary to reveal therapeutic hypothermia as a trigger for severe coagulopathies in asphyxiated neonates, especially in those with sepsis and overt coagulopathy prior to therapeutic hypothermia.

Human protein C concentrate in the treatment of purpura fulminans: a retrospective analysis of safety and outcome in 94 pediatric patients.

INTRODUCTION: Purpura fulminans (PF) is a devastating complication of uncontrolled systemic inflammation, associated with high incidence of amputations, skin grafts and death. In this study, we aimed to clarify the clinical profile of pediatric patients with PF who improved with protein C (PC) treatment, explore treatment effects and safety, and to refine the prognostic significance of protein C plasma levels. METHODS: In Germany, patients receiving protein C concentrate (Ceprotin, Baxter AG, Vienna, Austria) are registered. The database was used to locate all pediatric patients with PF treated with PC from 2002 to 2005 for this national, retrospective, multi-centered study. RESULTS: Complete datasets were acquired in 94 patients, treated in 46 centers with human, non-activated protein C concentrate for purpura fulminans. PC was given for 2 days (median, range 1-24 days) with a median daily dose of 100 IU/kg. Plasma protein C levels increased from a median of 27% to a median of 71% under treatment. 22.3% of patients died, 77.7% survived to discharge. Skin grafts were required in 9.6%, amputations in 5.3%. PF recovered or improved in 79.8%, remained unchanged in 13.8% and deteriorated in 6.4%. Four adverse events occurred in 3 patients, none classified as severe. Non-survivors had lower protein C plasma levels (P < 0.05) and higher prevalence of coagulopathy at admission (P < 0.01). Time between admission and start of PC substitution was longer in patients who died compared to survivors (P = 0.03). CONCLUSIONS: This retrospective dataset shows that, compared to historic controls, only few pediatric patients with PF under PC substitution needed dermatoplasty and/or amputations. Apart from epistaxis, no bleeding was observed. Although the data comes from a retrospective study, the evidence we present suggests that PC had a beneficial impact on the need for dermatoplasty and amputations, pointing to the potential value of carrying out a prospective randomised controlled trial.

Disseminated intravascular coagulation in term and preterm neonates.

Among critically ill patients, the risk of developing disseminated intravascular coagulation (DIC) is probably highest in neonates. Low plasma reserves in pro- and anticoagulant coagulation factors, intravascular volume contraction after birth, and a high incidence of hypoxia and sepsis in critically ill newborns rapidly lead to a decompensation of the coagulation system in this population. Global coagulation tests and single-factor plasma levels have to be interpreted in the context of age-corrected normal ranges. Platelet consumption and reduced protein C plasma levels have diagnostic value; the latter also has prognostic potential in neonates with DIC and sepsis. Therapeutic success relies heavily on reversal of the underlying condition. Some coagulation-specific therapies have been explored in small studies and case series with varying success and sometimes conflicting results. Therefore, larger controlled trials in this common and serious condition are urgently needed.

Intracerebral mass bleeding in a term neonate: manifestation of hereditary protein S deficiency with a new mutation in the PROS1 gene.

BACKGROUND: Vitamin K deficiency is the major cause of coagulopathy-induced intracranial bleeding in term neonates and is considered first in any term neonate with severe hemorrhage. The most common manifestation of hereditary prothrombotic disorders during the neonatal period is thrombosis of the A. cerebri media or sinus thrombosis. CASE REPORT: A 4-day-old newborn was admitted with seizures and hemorrhagic shock. Ultrasound revealed a left-sided intraparenchymatous bleeding. MRI findings supported a subarachnoidal and intracerebral mass bleeding. Vitamin K deficiency-related bleeding or hemophiliac diseases were excluded; however, homozygous protein S deficiency with a new mutation in the protein S (PROS1) gene (c.701A>G, p.Tyr234Cys) was found. The patient experienced an additional thrombosis of the A. abdominalis and expired. CONCLUSION: Congenital prothrombotic disorders have to be considered in the differential diagnosis of neonatal intracranial hemorrhage. This newly described mutation in the PROS1 gene (c.701A>G, p.Tyr234Cys) appears to be of clinical relevance.

Protein C preserves microcirculation in a model of neonatal septic shock.

OBJECTIVES: Sepsis remains a disease with a high mortality in neonates. Microcirculatory impairment plays a pivotal role in the development of multiorgan failure in septic newborns. The hemodynamic effects of recombinant activated protein C (rhAPC) were tested in an animal model of neonatal septic shock focusing on intestinal microcirculation. MATERIALS AND METHODS: Endotoxic shock was triggered by intravenous application of Escherichia coli lipopolysaccarides in newborn piglets. Thereafter, five animals received a continuous infusion of 24 microg/kg/h rhAPC, and five received vehicle for control. Over the course of three hours, intestinal microcirculation was assessed by intravital microscopy every 30 min. Macrocirculation and blood counts were monitored simultaneously. RESULTS: After a short hypotensive period in all animals, the arterial blood pressure returned to baseline in the rhAPC-treated piglets, whereas the hypotension became increasingly severe in the controls. By 90 min, mean blood pressure in the controls was significantly lower than in the treatment group. Similar observations were made regaring microcirculation. After an early impairment in all study animals, functional capillary density and intestinal microcirculatory red blood cell velocity and red blood cell flow recovered in the rhAPC group, but deteriorated further in the control piglets. CONCLUSION: Recombinant activated protein C protects macro- and microcirculation from endotoxic shock.

Incidence and clinical outcome of cytomegalovirus transmission via breast milk in preterm infants

AIM: To evaluate incidence, timing and clinical relevance of acquired human cytomegalovirus (HCMV) infection in preterm infants. METHODS: The prospective longitudinal study included preterm infants

Recombinant activated Factor VII as a hemostatic agent in very low birth weight preterms with gastrointestinal hemorrhage and disseminated intravascular coagulation.

OBJECTIVE: Acute hemorrhage in preterm infants leads immediately to a life-threatening event because of the small circulating blood volume. The beneficial use of recombinant activated Factor VII (rFVIIa; NovoSeven, NovoNordisk, Gentofte, Denmark) as hemostatic treatment in neonates with hemorrhagic shock has been described. Necrotizing enterocolitis is a challenge in neonatology as the disease represents one of the leading causes of mortality in preterm infants. We report on the use of rFVIIa in very low birth weight (<1500 g), preterms with intestinal hemorrhage, and disseminated intravascular coagulation (DIC). DESIGN: Retrospective analysis of 5 cases. PATIENTS: Five preterm infants