Early postnatal high-dose fat-soluble enteral vitamin A supplementation for moderate or severe bronchopulmonary dysplasia or death in extremely low birthweight infants (NeoVitaA): a multicentre, randomised, parallel-group, double-blind, placebo-controlled, investigator-initiated phase 3 trial.

BACKGROUND: Vitamin A plays a key role in lung development, but there is no consensus regarding the optimal vitamin A dose and administration route in extremely low birthweight (ELBW) infants. We aimed to assess whether early postnatal additional high-dose fat-soluble enteral vitamin A supplementation versus placebo would lower the rate of moderate or severe bronchopulmonary dysplasia or death in ELBW infants receiving recommended basic enteral vitamin A supplementation. METHODS: This prospective, multicentre, randomised, parallel-group, double-blind, placebo-controlled, investigator-initiated phase 3 trial conducted at 29 neonatal intensive care units in Austria and Germany assessed early high-dose enteral vitamin A supplementation (5000 international units [IU]/kg per day) or placebo (peanut oil) for 28 days in ELBW infants. Eligible infants had a birthweight of more than 400 g and less than 1000 g; gestational age at birth of 32+0 weeks postmenstrual age or younger; and the need for mechanical ventilation, non-invasive respiratory support, or supplemental oxygen within the first 72 h of postnatal age after admission to the neonatal intensive care unit. Participants were randomly assigned by block randomisation with variable block sizes (two and four). All participants received basic vitamin A supplementation (1000 IU/kg per day). The composite primary endpoint was moderate or severe bronchopulmonary dysplasia or death at 36 weeks postmenstrual age, analysed in the intention-to-treat population. This trial was registered with EudraCT, 2013-001998-24. FINDINGS: Between March 2, 2015, and Feb 27, 2022, 3066 infants were screened for eligibility at the participating centres. 915 infants were included and randomly assigned to the high-dose vitamin A group (n=449) or the control group (n=466). Mean gestational age was 26·5 weeks (SD 2·0) and mean birthweight was 765 g (162). Moderate or severe bronchopulmonary dysplasia or death occurred in 171 (38%) of 449 infants in the high-dose vitamin A group versus 178 (38%) of 466 infants in the control group (adjusted odds ratio 0·99, 95% CI 0·73-1·55). The number of participants with at least one adverse event was similar between groups (256 [57%] of 449 in the high-dose vitamin A group and 281 [60%] of 466 in the control group). Serum retinol concentrations at baseline, at the end of intervention, and at 36 weeks postmenstrual age were similar in the two groups. INTERPRETATION: Early postnatal high-dose fat-soluble enteral vitamin A supplementation in ELBW infants was safe, but did not change the rate of moderate or severe bronchopulmonary dysplasia or death and did not substantially increase serum retinol concentrations. FUNDING: Deutsche Forschungsgemeinschaft and European Clinical Research Infrastructures Network (ECRIN).

Does Accidental Hypothermia Increase Morbidity and Mortality in Mature Neonates?

Accidental hypothermia in mature neonates requiring hospitalization is a clinical complication that has not been studied in detail. In the present study, the effect of accidental hypothermia on common morbidity in neonates in the postnatal period was investigated. We did temperature measurements in 616 mature neonates after birth, after transfer to the maternity ward and at check-up at age of 48-72 hours of life. Additionally, nurses checked temperature until discharge at every diaper change in 302 of all included neonates who were small for gestational age (SGA) or whose mothers had green fluid or premature rupture of membranes (PROM). We investigated if there was a correlation between infection, hyperbilirubinemia, hypoglycemia, SGA, gestational diabetes, PROM, green amniotic fluid, positive GBS status of the mother, and accidental hypothermia in the first 48-72 hours of life. Mature neonates showed transient accidental hypothermia in the first 24 hours of life. No significant correlation between infection (p=0.571), hyperbilirubinemia (p=0.837), hypoglycemia (p=0.072), and accidental hypothermia could be seen. There was a significant correlation between SGA (p=0.020), PROM (p=0.008), and accidental hypothermia, while hyperthermia was associated with infection (p=0.009) and green amniotic fluid (p=0.004). SGA and PROM represent perinatal risk factors for postnatal transient accidental hypothermia in mature neonates. Increased morbidity or mortality associated with postnatal accidental hypothermia has not been demonstrated.Akzidentelle Hypothermie bei Reifgeborenen, die einer Hospitalisierung bedürfen, ist eine bisher nicht näher analysierte klinische Komplikation. In der vorliegenden Arbeit wurde die Abhängigkeit einer akzidentellen Hypothermie von typischen Erkrankungen der Postnatalperiode untersucht. Wir führten bei 616 Reifgeborenen Temperaturmessungen nach Geburt, nach Verlegung auf die Wochenstation und bei der Vorsorgeuntersuchung U2 durch. Zusätzlich kontrollierten wir bei 302 der 616 Neugeborenen mit Small for gestational age (SGA), grünem Fruchtwasser oder vorzeitigem Blasensprung (PROM) die Temperatur bei jedem Windelwechsel bis zur Entlassung. Wir untersuchten, ob es einen Zusammenhang zwischen Infektion, Hyperbilirubinämie, Hypoglykämie, SGA, Gestationsdiabetes, PROM, grünem Fruchtwasser, positivem GBS-Status der Mutter und akzidenteller Auskühlung innerhalb der ersten 48-72 Lebensstunden gab. Reifgeborene zeigten in den ersten 24 Lebensstunden transiente akzidentelle Hypothermien. Es konnte kein signifikanter Zusammenhang zwischen Infektion (P=0.571), Hyperbilirubinämie (p=0.837), Hypoglykämie (p=0.072) und akzidenteller Hypothermie festgestellt werden. Es bestand ein signifikanter Zusammenhang zwischen SGA (p=0.020), PROM (p=0.008) und akzidenteller Hypothermie, während Hyperthermie war mit Infektion (p=0.009) und grünem Fruchtwasser (p=0.004) assoziiert war. SGA und PROM stellen perinatale Risikofaktoren für postnatale transiente, akzidentelle Hypothermien bei Reifgeborenen dar. Eine erhöhte Morbidiät bzw. Mortalität im Zusammenhang mit postnataler akzidenteller Hypothermie konnte nicht nachgewiesen werden.

"Multisystem Inflammatory Syndrome in Children" (MIS-C) after COVID-19 Infection in the Metropolitan Area of Nuremberg-Erlangen, Germany-Expectations and Results of a Two-Year Period.

BACKGROUND: Multisystemic Inflammatory Syndrome in children (MIS-C) is a rare autoimmune disorder occurring after a latency period following acute SARS-CoV-2 infection. The therapeutic regime of MIS-C is adapted to the therapy of the Kawasaki disease, as clinical symptoms are similar. Since the Kawasaki disease can potentially result in severe symptoms, which may even affect long-term health, it is essential to gain further knowledge about MIS-C. Thus, we aimed to investigate the incidence, symptoms, therapeutical procedure and outcome of MIS-C patients in the metropolitan area of Nuremberg-Erlangen during the SARS-CoV2 pandemic. MATERIAL AND METHODS: Retrospective analysis of clinical charts of MIS-C patients was carried out at three children's hospitals covering the medical care of the metropolitan area of Nuremberg-Erlangen in Germany. Demographic characteristics and symptoms at first visit, their clinical course, therapeutic regime and outcome were recorded within the time period January 2021-December 2022. RESULTS: Analysis of 10 patients (5 male, 5 female) with MIS-C resulting in an incidence of 2.14/100.000 children. The median time between COVID-19 infection and admission to hospital was 5 weeks. The median age was 7 years. Symptoms comprised fever (100%), rash (70%), bilateral non-purulent conjunctivitis (70%) and urticaria (20%). At the time of presentation, diagnosis-defining inflammation parameters were increased and the range for C-reactive protein was 4.13 mg/dL to 28 mg/dL, with a median of 24.7 mg/dL. Procalcitonin was initially determined in six patients (1.92 ng/mL to 21.5 ng/mL) with a median value of 5.5 pg/mL. Two patients displayed leukocytosis and two displayed leukopenia. None of the patients presented coronary pathologies. Nine of the ten patients received intravenous immunoglobulin (IVIG) therapy. In addition, patients received intravenous steroids (80%) and acetylsalicylic acid (80%). CONCLUSION: SARS-CoV virus may rarely exert multiorgan manifestations due to hyperinflammatory immunological processes. Within two years of the COVID-19 pandemic, we identified ten patients with COVID-induced MIS-C in the metropolitan area Nuremberg-Erlangen. In the description of the patient collective, we can confirm that MIS-C is distinguished from the Kawasaki disease by the lack of coronary manifestations. Interestingly, although having monitored all pediatric facilities in the investigated area, we find lower incidences of MIS-C compared to findings in the literature. In conclusion, an overestimation of incidences in the upcoming MIS-C during the pandemic needs to be considered.

[Pediatric infectious emergencies-from febrile seizure to purpura fulminans]. / Infektiologische Kindernotfälle ­ vom Fieberkrampf bis zur Purpura fulminans.

Febrile seizures, which are relatively common in young children, are often triggered by an infection and resolve quickly. Prompt presentation to a pediatric department is mandatory after any first seizure and every time for children ≤ 12 months. Central nervous system (CNS) diseases in childhood are able to cause seizures or other neurological disorders. Even the slightest suspicion of a seizure with CNS involvement must be promptly treated. In case of doubt, both an antiviral and an antibacterial treatment are started in parallel, which can be stopped after detecting the pathogen. Lumbar puncture is strictly indicated unless there are contraindications. Meningococcal sepsis is a severe clinical feature comprising high fever, chills and disorders of consciousness. The first skin symptoms are petechiae as a red flag sign. With progression, potentially lethal purpura fulminans may develop. Waterhouse-Friderichsen syndrome is a severe complication of acute bacterial meningitis. Lethality rate is 35%. The pediatric assessment triangle and the ABCDE algorithm help to identify critically ill children in a standardized, structured, and rapid manner.

[Breathing disorders in children]. / Atemstörungen bei Kindern.

Breathing disorders in children are one of the most common challenges for both parents and physicians. The first step should always consist of the initial clinical assessment concerning the potentially critically ill patient. Using the pediatric assessment triangle (PAT), the rapid evaluation of airway and breathing is crucial. Although the etiology of pediatric breathing disorders is manifold, we would like to focus on common diagnoses. Based on the three leading symptoms stridor, wheeze, and tachypnea, the most important diseases of pediatric patients are presented and initial treatment steps are discussed. We target crucial, life-saving, basic medical procedures that should be mastered and performed in and also outside of specialized centers or pediatric units.

Umbilical venous catheter- and peripherally inserted central catheter-associated complications in preterm infants with birth weight < 1250 g : Results from a survey in Austria and Germany.

BACKGROUND AND OBJECTIVE: Umbilical venous catheters (UVC) and peripherally inserted central catheters (PICC) are commonly used in preterm infants but have been associated with a number of serious complications. We performed a survey in Austria and Germany to assess the use of UVCs and PICCs in preterm infants with a birth weight < 1250 g and associated rates of catheter-related adverse events. METHODS: Electronic survey of participating centers of the NeoVitaA trial. Main outcome parameter was the reported rates of UVC- and PICC-associated complications (infection, thrombosis, emboli, organ injury, arrhythmia, dislocation, miscellaneous). RESULTS: In total, 20 neonatal intensive care units (NICU) providing maximal intensive care in Austria and Germany (level I) were contacted, with a senior neonatologist response rate of 12/20 (60%). The reported rates for UVC with a dwell time of 1-10 days were bacterial infection: 4.2 ± 3.4% (range 0-10%); thrombosis: 7.3 ± 7.1% (0-20%); emboli: 0.9 ± 2.0% (0-5%); organ injury: 1.1 ± 1.9% (0-5%); cardiac arrhythmia: 2.2 ± 2.5% (0-5%); and dislocation: 5.4 ± 8.7% (0-30%); and for PICCs with a dwell time of 1-14 days bacterial infection: 15.0 ± 3.4% (range 2.5-30%); thrombosis; 4.3 ± 3.5% (0-10%); emboli: 0.8 ± 1.6% (0-5%); organ injury: 1.5 ± 2.3% (0-5%); cardiac arrhythmia: 1.5 ± 2.3% (0-5%), and dislocation: 8.5 ± 4.6% (0-30%). CONCLUSION: The catheter-related complication rates reported in this survey differed between UVCs and PICCs and were higher than those reported in the literature. To generate more reliable data on this clinically important issue, we plan to perform a large prospective multicenter randomized controlled trial investigating the non-inferiority of a prolonged UVC dwell time (up to 10 days) against the early change (up to 5 days) to a PICC.

Pharmacokinetic/Pharmacodynamic Modelling of Allopurinol, its Active Metabolite Oxypurinol, and Biomarkers Hypoxanthine, Xanthine and Uric Acid in Hypoxic-Ischemic Encephalopathy Neonates.

BACKGROUND: Allopurinol, an xanthine oxidase (XO) inhibitor, is a promising intervention that may provide neuroprotection for neonates with hypoxic-ischemic encephalopathy (HIE). Currently, a double-blind, placebo-controlled study (ALBINO, NCT03162653) is investigating the neuroprotective effect of allopurinol in HIE neonates. OBJECTIVE: The aim of the current study was to establish the pharmacokinetics (PK) of allopurinol and oxypurinol, and the pharmacodynamics (PD) of both compounds on hypoxanthine, xanthine, and uric acid in HIE neonates. The dosage used and the effect of allopurinol in this population, either or not undergoing therapeutic hypothermia (TH), were evaluated. METHODS: Forty-six neonates from the ALBINO study and two historical clinical studies were included. All doses were administered on the first day of life. In the ALBINO study (n = 20), neonates received a first dose of allopurinol 20 mg/kg, and, in the case of TH (n = 13), a second dose of allopurinol 10 mg/kg. In the historical cohorts (n = 26), neonates (all without TH) received two doses of allopurinol 20 mg/kg in total. Allopurinol and oxypurinol population PK, and their effects on inhibiting conversions of hypoxanthine and xanthine to uric acid, were assessed using nonlinear mixed-effects modelling. RESULTS: Allopurinol and oxypurinol PK were described by two sequential one-compartment models with an autoinhibition effect on allopurinol metabolism by oxypurinol. For allopurinol, clearance (CL) was 0.83 L/h (95% confidence interval [CI] 0.62-1.09) and volume of distribution (Vd) was 2.43 L (95% CI 2.25-2.63). For metabolite oxypurinol, CL and Vd relative to a formation fraction (fm) were 0.26 L/h (95% CI 0.23-0.3) and 11 L (95% CI 9.9-12.2), respectively. No difference in allopurinol and oxypurinol CL was found between TH and non-TH patients. The effect of allopurinol and oxypurinol on XO inhibition was described by a turnover model of hypoxanthine with sequential metabolites xanthine and uric acid. The combined allopurinol and oxypurinol concentration at the half-maximal XO inhibition was 0.36 mg/L (95% CI 0.31-0.42). CONCLUSION: The PK and PD of allopurinol, oxypurinol, hypoxanthine, xanthine, and uric acid in neonates with HIE were described. The dosing regimen applied in the ALBINO trial leads to the targeted XO inhibition in neonates treated with or without TH.

Glomerular Filtration Rate in Asphyxiated Neonates Under Therapeutic Whole-Body Hypothermia, Quantified by Mannitol Clearance.

BACKGROUND: Therapeutic hypothermia (TH) is an established intervention to improve the outcome of neonates with moderate-to-severe hypoxic-ischemic encephalopathy resulting from perinatal asphyxia. Despite this beneficial effect, TH may further affect drug elimination pathways such as the glomerular filtration rate. OBJECTIVES: The objective of this study was to quantify the effect of TH in addition to asphyxia on mannitol clearance as a surrogate for the glomerular filtration rate. METHODS: The effect of asphyxia and TH (mild vs moderate/severe) on mannitol clearance was assessed using a population approach, based on mannitol observations collected in the ALBINO (ALlopurinol in addition to TH for hypoxic-ischemic Brain Injury on Neurocognitive Outcome) trial, as some were exposed to a second dose of 10 mg/kg intravenous mannitol as placebo to ensure blinding. Pharmacokinetic analysis and model development were conducted using NONMEM version 7.4. RESULTS: Based on 77 observations from 17 neonates (TH = 13), a one-compartment model with first-order linear elimination best described the observed data. To account for prenatal glomerular filtration rate maturation, both birthweight and gestational age were implemented as clearance covariates using an earlier published three-quarters power function and a sigmoid hyperbolic function. Our final model predicted a mannitol clearance of 0.15 L/h for a typical asphyxia neonate (39.5 weeks, birthweight 3.25 kg, no TH), lower than the reported value of 0.33 L/h for a healthy neonate of similar age and weight. By introducing TH as a binary covariate on clearance, the additional impact of TH on mannitol clearance was quantified (60% decrease). CONCLUSIONS: Mannitol clearance was decreased by approximately 60% in neonates undergoing TH, although this is likely confounded with asphyxia severity. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03162653.

Acute urinary retention in children.

BACKGROUND: Acute urinary retention is a common emergency in adult patients, foremost in older men. In childhood urinary retention is a rare entity with only sparse literature on the etiology. OBJECTIVE: To assess the etiology and treatment of acute urinary retention in the pediatric population and assess age and sex distribution. STUDY DESIGN: A retrospective analysis of all patients admitted to our emergency department with acute urinary retention between 2005 and 2019 was performed. Exclusion criteria were newborns (because of physiologic postnatal oliguria) and postoperative urinary retention during the same hospital stay. RESULTS: 113 children with acute urinary retention (ICD: R33) meeting the above criteria were identified. 16 Patients were excluded because of incomplete medical charts. 97 children were included into the study (age 0.5-18.3 years, mean age 5.3 years). 89 patients had one episode, 8 patients two episodes. A peak around the third year of age was observed. Sex ratio showed a 2:1 male to female distribution. Most common etiology was balanoposthitis (15.5%) and acute constipation/fecal impaction (15.5%). Traumatic urinary retention was found in 11.4% of the cases. Urinary tract infection were found 7.2%. No underlying reason could be found in 12.4% (idiopathic urinary retention). Other causes included febrile non-urinary infection (8.2%), subvesical obstruction (4.1%), vulvovaginitis (3.1%) and urethritis (2.1%). In 50% of the cases of urinary retention under 1 year of age (2 out of 4) an underlying tumor (rhabdomyosarcoma, sacral teratoma) was identified. DISCUSSION: Age and sex distribution were similar to previously published series; however, this study shows a marked difference concerning the etiology: e. g. we identified a significantly higher proportion of functional disorders as a reason for acute urinary retention in childhood. It is hypothesized that this is partly because previously published studies originate from areas (USA, Israel, Iran) with different socio-demographic and cultural background. CONCLUSION: AUR in children is a rare condition with very heterogeneous causes. Although the majority of cases exhibit mild underlying conditions, serious reasons, such as malignant diseases especially in the first year of life, must be excluded. AUR relief without catheterization is a child-friendly approach in cases of mild inflammatory or functional disorders and can help to minimize traumatization.

[Is the Quality Guideline of Care Delivery of Preterm and Mature Infants (QFR-RL) of the Federal Joint Committee (G-BA) a Quality Risk? - An Analysis of the Fulfillment Rate and the Consequences for Care Delivery to Other IC Patients and Imminent Premature Infants at a Regional Network of Perinatal Centers]. / Qualitätssicherungsrichtlinie Früh- und Reifgeborene des Gemeinsamen Bundesausschusses als Qualitätsrisiko?

BACKGROUND: The quality guideline for care delivery to preterm and mature infants (QFR-RL) places high demands on perinatal centers. In this analysis, the degree of fulfillment was determined. Additionally, care delivery to further patient groups and sufficient nursing staff capacity for care delivery to imminent preterm infants (FG) were evaluated. METHODS: A network of 4 perinatal centers (level 1) with about 10,000 births per year supplied the data on the ratio of 1:1/1:2-care infants, patients per nurse, and nursing staff capacity. This data was statistically evaluated by center, shift, and week day over a period of 5 months for compliance with QFR-RL and DGPM recommendations. Furthermore, imminent preterm infants were recorded and compared with available nursing staff capacity. RESULTS: In total, the QFR-RL was fulfilled in 88% of shifts (n=1,584). Only one center reached the required 95%. The degree of fulfillment and the number of staff nurses declined from late to night shifts (p<0.001). The ratio of 1:1-care infants was significantly higher when demands were not fulfilled (p<0.001). Only 14.1% of imminent preterm infants could have been attended in accordance with the QFR-RL. CONCLUSION: 1:1 care as well as lower nurse staffing in late and night shifts lead to non-fulfillment of requirements and poorer care delivery to other intensive care patients. This was also reflected in the lower degree of fulfillment of DGPM recommendations. Sufficient nursing staff capacity was rare with the consequence that it was almost impossible to deliver care to imminent preterm infants per the guideline.

Small direct right ventricular cardiac metastasis of osteosarcoma in a 10-year-old boy affirmed by cardiac MRI.

BACKGROUND: Metastatic osteosarcoma with direct cardiac involvement is an exceptionally rare finding. Reliable detection of cardiac metastases is known to be crucial for patients therapy and prognosis. CASE SUMMARY: In a 10-year-old boy affected by osteosarcoma of the left femur, a baseline Fluorine-18-fluorodeoxy-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) was performed to assess the full extent of disease. Whole-body scan detected numerous bone metastases together with a single pulmonary metastasis. Moreover, increased tracer uptake was observed in the intracavitary right cardiac ventricle in the position of a subtle spot of calcification. Because of nondetectability of a cavitary lesion on echocardiography, cardiac magnetic resonance imaging (CMRI) examination was performed to evaluate cardiac 18F-FDG PET/CT finding. CMRI revealed a small nodule in the right ventricle attached to the trabeculae, highly suspicious of a direct cardiac metastasis. After 4 cycles of chemotherapy, complete regression of tracer uptake of the lesion was observed on a follow-up 18F-FDG PET/CT scan. CONCLUSION: CMRI is able to detect even small, clinically asymptomatic cardiac metastases in young patients affected by osteosarcoma.

Improved visualization of peripherally inserted central catheters on chest radiographs of neonates using fractional multiscale image processing.

BACKGROUND: Peripherally inserted central catheters (PICCs) provide secure intravenous access for the delivery of life-sustaining medications and nutrition. They are commonly used in pediatrics. Confirmation of correct central catheter tip position is crucial. Verification is usually done by a radiograph. The aim of this study is to evaluate the ability of Fractional Multiscale image Processing (FMP) to detect PICC tips on the digital chest radiographs of neonates. METHODS: A total of 94 radiographs of 47 patients were included in the study. 29 patients were male, 18 were female. The mean age of all examined children was 9.2 days (range 0-99 days). In total, six readers (two radiologists, two residents in radiology, one last year medical student, one neonatologist) evaluated 94 unprocessed and catheter-enhanced radiographs using a 5-point Likert scale (1 = poor catheter tip visualization, 5 = excellent catheter tip visualization). Additionally, the two radiologists evaluated the diagnostic confidence for chest pathologies using a 5-point Likert scale (1 = poor diagnostic confidence, 5 = excellent diagnostic confidence). Radiographs were evaluated on a dedicated workstation. RESULTS: In all cases, the catheter-enhanced radiograph rated higher than (n = 471), or equal (n = 93) to, the unprocessed radiograph when visualizing catheter tips. 87% of the catheter-enhanced radiographs obtained a rating of 4 or higher, while only 42% of unprocessed radiographs received 4 or more points. Regarding diagnostic confidence for chest pathologies one radiologist rated two catheter-enhanced radiographs higher than the unprocessed radiographs, while all other 186 evaluations rated the catheter-enhanced radiographs equal to (n = 78) or lower than (n = 108) the unprocessed radiographs. Only 60% of the catheter-enhanced radiographs yielded a diagnostic confidence of 4 or higher, while 90% of the unprocessed images received 4 or more points. CONCLUSION: Catheter-enhanced digital chest radiographs demonstrate improved visualization of low contrast PICC tips in neonates compared to unprocessed radiographs. Furthermore, they enable detection of accompanying chest pathologies. However, definitive diagnosis of chest pathologies should be made on unprocessed radiographs.

[Chronic Headache in Children and Adolescents]. / Chronische Kopfschmerzen bei Kindern und Jugendlichen.

Primary headache disorders such as migraine and tension-type headache begin as early as childhood or adolescence. Prevalence increases during primary school and adolescence. In tension-type headache, central pain sensitization and activation of central nociceptive neurons plays an important role. Migraine is a primary brain disorder with abnormalities in pain modulating systems and cortical stimulus processing. Bio-psycho-social factors play a decisive role in both types of headache. Secondary headaches due to an inflammatory or a structural brain alteration are rare. Diagnosis is based on clinical criteria. Typical recurrent headaches are diagnosed by patient's history and physical examination. In case of abnormalities, further diagnostic is needed. Treatment of tension-type headache is focused on multimodal pain therapy, treatment of migraine is focused on medication of attacks and secondary headaches need treatment of the underlying disease. Treatment goals are the reduction of pain perception, promotion of control and self-efficacy experiences, the increase of physical performance as well as the resumption of normal everyday structures and social contacts as a prerequisite for an increasing pain reduction.

Influence of factor XIII activity on post-operative transfusion in congenital cardiac surgery-A retrospective analysis.

OBJECTIVES: Coagulation factor XIII (FXIII) plays a key role in fibrin clot stabilization-an essential process for wound healing following cardiothoracic surgery. However, FXIII deficiency as a risk for post-operative bleeding in pediatric cardiac surgery involving cardiopulmonary bypass (CPB) for congenital heart disease (CHD) is controversially discussed. Thus, as primary outcome measures, we analyzed the association of pre-operative FXIII activity and post-operative chest tube drainage (CTD) loss with transfusion requirements post-operatively. Secondary outcomes included the influence of cyanosis and sex on transfusion. METHODS: Our retrospective analysis (2009-2010) encompassed a single center series of 76 cardio-surgical cases with CPB (0-17 years, mean age 5.61 years) that were post-operatively admitted to our pediatric intensive care unit (PICU). The observational period was 48 hours after cardiac surgery. Blood cell counts and coagulation status, including FXIII activity were routinely performed pre- and post-operatively. The administered amount of blood products and volume expanders was recorded electronically, along with the amount of CTD loss. Uni- and multivariate logistic regression analysis was performed to calculate the associations (odds ratios) of variables with post-operative transfusion needs. RESULTS: FXIII activities remained stable following CPB surgery. There was no association of pre- and post-operative FXIII activities and transfusion of blood products or volume expanders in the first 48 hours after surgery. Similarly, FXIII showed no association with CTD loss. Cyanosis and female sex were associated with transfusion rates. CONCLUSIONS: Although essentially involved in wound healing and clotting after surgery, FXIII activity does not serve as a valid predictor of post-operative transfusion need.

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

AIM: Continuous pain occurs routinely, even after invasive procedures, or inflammation and surgery, but clinical practices associated with assessments of continuous pain remain unknown. METHODS: A prospective cohort study in 243 neonatal intensive care units (NICUs) from 18 European countries recorded the frequency of pain assessments, use of mechanical ventilation, sedation, analgesia or neuromuscular blockade for each neonate for up to 28 days after NICU admission. RESULTS: Only 2113 of 6648 (31.8%) of neonates received assessments of continuous pain, occurring variably among tracheal ventilation (TrV, 46.0%), noninvasive ventilation (NiV, 35.0%) and no ventilation (NoV, 20.1%) groups (p < 0.001). Daily assessments for continuous pain occurred in only 10.4% of all neonates (TrV: 14.0%, NiV: 10.7%, NoV: 7.6%; p < 0.001). More frequent assessments of continuous pain occurred in NICUs with pain guidelines, nursing champions and surgical admissions (all p < 0.01), and for newborns <32 weeks gestational age, those requiring ventilation, or opioids, sedatives-hypnotics, general anaesthetics (O-SH-GA) (all p < 0.001), or surgery (p = 0.028). Use of O-SH-GA drugs increased the odds for pain assessment in the TrV (OR:1.60, p < 0.001) and NiV groups (OR:1.40, p < 0.001). CONCLUSION: Assessments of continuous pain occurred in less than one-third of NICU admissions and daily in only 10% of neonates. NICU clinical practices should consider including routine assessments of continuous pain in newborns.

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 Community's Seventh Framework Programme.

Autoselection of cytoplasmic yeast virus like elements encoding toxin/antitoxin systems involves a nuclear barrier for immunity gene expression.

Cytoplasmic virus like elements (VLEs) from Kluyveromyces lactis (Kl), Pichia acaciae (Pa) and Debaryomyces robertsiae (Dr) are extremely A/T-rich (>75%) and encode toxic anticodon nucleases (ACNases) along with specific immunity proteins. Here we show that nuclear, not cytoplasmic expression of either immunity gene (PaORF4, KlORF3 or DrORF5) results in transcript fragmentation and is insufficient to establish immunity to the cognate ACNase. Since rapid amplification of 3' ends (RACE) as well as linker ligation of immunity transcripts expressed in the nucleus revealed polyadenylation to occur along with fragmentation, ORF-internal poly(A) site cleavage due to the high A/T content is likely to prevent functional expression of the immunity genes. Consistently, lowering the A/T content of PaORF4 to 55% and KlORF3 to 46% by gene synthesis entirely prevented transcript cleavage and permitted functional nuclear expression leading to full immunity against the respective ACNase toxin. Consistent with a specific adaptation of the immunity proteins to the cognate ACNases, cross-immunity to non-cognate ACNases is neither conferred by PaOrf4 nor KlOrf3. Thus, the high A/T content of cytoplasmic VLEs minimizes the potential of functional nuclear recruitment of VLE encoded genes, in particular those involved in autoselection of the VLEs via a toxin/antitoxin principle.

Improved closure of patent ductus arteriosus with high doses of ibuprofen.

The patent ductus arteriosus (PDA) is associated with various complications of prematurity. Cyclooxygenase-inhibitors are the first-line intervention for closure of the PDA. However, the rates of PDA closure still are unsatisfactory. Therefore, an individual trial was performed by changing the strategy for treating neonates with ibuprofen to induce the closure of PDA. In a retrospective study, patients receiving 20, 10, and 10 mg/kg bodyweight ibuprofen (group 1) were compared by chart review with those receiving 10, 5, 5 mg/kg (group 2). The rate of PDA closure, the incidence of side effects related to the use of ibuprofen, and the need for surgical intervention for closure of the PDA were analyzed. A higher rate of closure after three doses in group 1 could be observed (60.9 vs 52.6%; p = 0.75), which was not significant but indicated a clear positive trend. If closure of the PDA was unsuccessful, intravenous ibuprofen was continued for an additional 2 days. After 5 days, 91.3% of PDA in group 1 was closed compared with 68.4% PDA in group 2. In summary, only 8.7% of the group 1 neonates needed surgical closure of PDA after insufficient medicamentous closure compared with 31.6% in group 2 (p = 0.25). Although not statistically significant, a clear positive trend for using the higher-dose medication can be seen. More work dealing with the limitations of a retrospective study must be done. Based on the data from this study, high-dose ibuprofen seems able to increase the rate of effective medicamentous PDA closure without any further unwanted side effects.

Intrauterine use of hyperconcentrated platelet concentrates collected with Trima Accel in a case of neonatal alloimmune thrombocytopenia.

BACKGROUND: Due to the threat of serious or fatal bleedings, fetuses with neonatal alloimmune thrombocytopenia (NAIT) may need intrauterine platelet (PLT) transfusions. To prevent a volume overload or an ABO minor mismatch, standard PLT concentrates need to be washed to increase the PLT concentration and to reduce the plasma content. Hyperconcentrated single-donor PLT concentrates (HCPs) are a therapeutic alternative. The first case of NAIT successfully treated with HCPs collected with the Trima Accel (TA; Gambro BCT) is reported. CASE REPORT: A 31-year-old woman with a history of NAIT in the preceding pregnancy underwent cordocentesis three times during her third pregnancy (30th, 31st, and 32nd weeks of gestation). NAIT was confirmed by marked fetal thrombocytopenia, a maternal anti-human PLT antigen (HPA)-1a-immunoglobulin G (titer 1:128), and the appropriate HPA genotype of the fetus and the parents. On each cordocentesis procedure, a distinct volume of a HPA-1a-negative HCP with a PLT concentration of 3 x 10(6) PLTs per microL was transfused resulting in high corrected count increments after 2 hours. The HCPs were transfused within 10 hours after collection. One day after the last cordocentesis procedure, a cesarean section was performed. The newborn did not show any bleeding signs, and the PLT count remained on normal levels and no further PLT transfusions were needed. CONCLUSION: HCPs collected with TA are a useful alternative to washed standard PLT concentrates without the need for further manipulation of the product after collection. Further in vitro and in vivo studies are needed, however, to make definite recommendations for the shelf life of these HCP.