Efficacy and Safety of Esmolol in Neonatal Cardiac Surgery with Cardiopulmonary Bypass (CPB) for d-Transposition of the Great Arteries (d-TGA).

OBJECTIVE: D-Transposition of the great arteries (d-TGA) is the most common congenital heart disease requiring surgical correction within the neonatal period. Sinus tachycardia often persists postoperatively, potentially affecting cardiac function. This study aimed to investigate the efficacy and safety of the short-acting beta-1-selective beta-blocker esmolol in controlling heart rate in neonatal cardiac surgery with cardiopulmonary bypass (CPB). METHODS: A retrospective cohort study was conducted on neonates undergoing surgery for d-TGA. The study cohort included 112 patients, divided into an esmolol intervention group (n = 57) and a control group (n = 55). Baseline characteristics, hemodynamic parameters and outcome measures were assessed. RESULTS: In the esmolol group, median heart rate at ICU admission was significantly higher compared to the control group (155 vs. 147 bpm, p = 0.018). After a median time of 11 h, heart rate was lower among the esmolol patients (135 vs. 144 bpm, p < 0.001). There were no differences in other hemodynamic parameters between the two groups. Patients treated with esmolol required longer catecholamine support while no difference regarding survival, duration of invasive ventilation and ICU stay were noticed. CONCLUSION: No relevant hemodynamic difference was seen between neonates treated with perioperative esmolol and the control group and outcome did not differ. This indicates non-inferiority of perioperative betablocker therapy in young age. Prospective and placebo-controlled assessment of perioperative esmolol therapy in neonates is needed.

Blocking metabotropic glutamate receptor subtype 7 (mGlu7) via the Venus flytrap domain (VFTD) inhibits amygdala plasticity, stress, and anxiety-related behavior.

The metabotropic glutamate receptor subtype 7 (mGlu7) is an important presynaptic regulator of neurotransmission in the mammalian CNS. mGlu7 function has been linked to autism, drug abuse, anxiety, and depression. Despite this, it has been difficult to develop specific blockers of native mGlu7 signaling in relevant brain areas such as amygdala and limbic cortex. Here, we present the mGlu7-selective antagonist 7-hydroxy-3-(4-iodophenoxy)-4H-chromen-4-one (XAP044), which inhibits lateral amygdala long term potentiation (LTP) in brain slices from wild type mice with a half-maximal blockade at 88 nm. There was no effect of XAP044 on LTP of mGlu7-deficient mice, indicating that this pharmacological effect is mGlu7-dependent. Unexpectedly and in contrast to all previous mGlu7-selective drugs, XAP044 does not act via the seven-transmembrane region but rather via a binding pocket localized in mGlu7's extracellular Venus flytrap domain, a region generally known for orthosteric agonist binding. This was shown by chimeric receptor studies in recombinant cell line assays. XAP044 demonstrates good brain exposure and wide spectrum anti-stress and antidepressant- and anxiolytic-like efficacy in rodent behavioral paradigms. XAP044 reduces freezing during acquisition of Pavlovian fear and reduces innate anxiety, which is consistent with the phenotypes of mGlu7-deficient mice, the results of mGlu7 siRNA knockdown studies, and the inhibition of amygdala LTP by XAP044. Thus, we present an mGlu7 antagonist with a novel molecular mode of pharmacological action, providing significant application potential in psychiatry. Modeling the selective interaction between XAP044 and mGlu7's Venus flytrap domain, whose three-dimensional structure is already known, will facilitate future drug development supported by computer-assisted drug design.

Adaptive Sampling of 3D Spatial Correlations for Focus+Context Visualization.

Visualizing spatial correlations in 3D ensembles is challenging due to the vast amounts of information that need to be conveyed. Memory and time constraints make it unfeasible to pre-compute and store the correlations between all pairs of domain points. We propose the embedding of adaptive correlation sampling into chord diagrams with hierarchical edge bundling to alleviate these constraints. Entities representing spatial regions are arranged along the circular chord layout via a space-filling curve, and Bayesian optimal sampling is used to efficiently estimate the maximum occurring correlation between any two points from different regions. Hierarchical edge bundling reduces visual clutter and emphasizes the major correlation structures. By selecting an edge, the user triggers a focus diagram in which only the two regions connected via this edge are refined and arranged in a specific way in a second chord layout. For visualizing correlations between two different variables, which are not symmetric anymore, we switch to showing a full correlation matrix. This avoids drawing the same edges twice with different correlation values. We introduce GPU implementations of both linear and non-linear correlation measures to further reduce the time that is required to generate the context and focus views, and to even enable the analysis of correlations in a 1000-member ensemble.

Interactive Focus+Context Rendering for Hexahedral Mesh Inspection.

The visual inspection of a hexahedral mesh with respect to element quality is difficult due to clutter and occlusions that are produced when rendering all element faces or their edges simultaneously. Current approaches overcome this problem by using focus on specific elements that are then rendered opaque, and carving away all elements occluding their view. In this work, we make use of advanced GPU shader functionality to generate a focus+context rendering that highlights the elements in a selected region and simultaneously conveys the global mesh structure and deformation field. To achieve this, we propose a gradual transition from edge-based focus rendering to volumetric context rendering, by combining fragment shader-based edge and face rendering with per-pixel fragment lists. A fragment shader smoothly transitions between wireframe and face-based rendering, including focus-dependent rendering style and depth-dependent edge thickness and halos, and per-pixel fragment lists are used to blend fragments in correct visibility order. To maintain the global mesh structure in the context regions, we propose a new method to construct a sheet-based level-of-detail hierarchy and smoothly blend it with volumetric information. The user guides the exploration process by moving a lens-like hotspot. Since all operations are performed on the GPU, interactive frame rates are achieved even for large meshes.

A Comparison of Rendering Techniques for 3D Line Sets With Transparency.

This article presents a comprehensive study of rendering techniques for 3D line sets with transparency. The rendering of transparent lines is widely used for visualizing trajectories of tracer particles in flow fields. Transparency is then used to fade out lines deemed unimportant, based on, for instance, geometric properties or attributes defined along with them. Accurate blending of transparent lines requires rendering the lines in back-to-front or front-to-back order, yet enforcing this order for space-filling 3D line sets with extremely high-depth complexity becomes challenging. In this article, we study CPU and GPU rendering techniques for transparent 3D line sets. We compare accurate and approximate techniques using optimized implementations and several benchmark data sets. We discuss the effects of data size and transparency on quality, performance, and memory consumption. Based on our study, we propose two improvements to per-pixel fragment lists and multi-layer alpha blending. The first improves the rendering speed via an improved GPU sorting operation, and the second improves rendering quality via transparency-based bucketing.

Successful Management of an Infant with Atypical Presentation of Alveolar Capillary Dysplasia with Misalignment of the Pulmonary Veins.

A newborn infant patient presented with persistent pulmonary hypertension. For right ventricular decompression, the ductus arteriosus was kept open by prostaglandin E 1 infusion and was stented at the age of 4 weeks during heart catheterization. The child was weaned from mechanical ventilation, since pulmonary functions were adequate. A small atrial septal defect was identified and closed in cardiac catheterization laboratory to decrease preductal hypoxemia. Diagnostic workup led to the diagnosis of alveolar capillary dysplasia with misalignment of the pulmonary veins. Suprasystemic pulmonary arterial hypertension with persisting nitric oxide dependency remained the leading symptoms. The child underwent bilateral lung transplantation at the age of 28 months. He is well at the age of 44 months.

Ketamine inhibits transcription factors activator protein 1 and nuclear factor-kappaB, interleukin-8 production, as well as CD11b and CD16 expression: studies in human leukocytes and leukocytic cell lines.

BACKGROUND: Recent data indicate that ketamine exerts antiinflammatory actions. However, little is known about the signaling mechanisms involved in ketamine-induced immune modulation. In this study, we investigated the effects of ketamine on lipopolysaccharide-induced activation of transcription factors activator protein 1 (AP-1) and nuclear factor-kappaB (NF-kappaB) in human leukocyte-like cell lines and in human blood neutrophils. METHODS: Electric mobility shift assays were used to investigate ketamine's effects on nuclear binding activity of both transcription factors in U937 cells, and a whole blood flow cytometric technique was used for AP-1 and NF-kappaB determination in leukocytes. Cell lines with different expression patterns of opioid and N-methyl-D-aspartate receptors were used for reverse transcription-polymerase chain reaction to investigate receptors involved in ketamine signaling. Ketamine's effect on interleukin-8 production was assessed in a whole blood assay. RESULTS: Ketamine inhibited both transcription factors in a concentration-dependent manner. These effects did not depend on opiate or N-methyl-D-aspartate receptors. Ketamine also reduced interleukin-8 production in whole blood and expression of CD11b and CD16 on neutrophils. CONCLUSION: The immunoinhibitory effects of ketamine are at least in part caused by inhibition of transcription factors NF-kappaB and AP-1, which regulate production of proinflammatory mediators. However, signaling mechanisms different from those present in the central nervous system are responsible for ketamine-mediated immunomodulation.

Tuberculosis-Associated HLH in an 8-Month-Old Infant: A Case Report and Review.

Hemophagocytic lymphohistiocytosis (HLH) is a rare immunological disease, which can be mistaken for sepsis easily. Among the infectious causes that may trigger secondary HLH, tuberculosis (TBC), a rather rare pathogen nowadays, is typical. To our knowledge, this is the first case report of an infant suffering from TBC-associated HLH-induced acute respiratory failure who was treated successfully using extracorporeal membrane oxygenation. An 8-month-old boy with fever (over the last 8 wk) and pancytopenia was transferred to our institution with acute respiratory failure and for extracorporeal membrane oxygenation therapy. Bone marrow biopsy revealed hemophagocytosis. Immunological work-up for familial HLH was negative. In a desperate search for the cause of secondary HLH, an interferon-gamma release assay for TBC returned positive. However, microscopy for acid-fast bacteria as well as polymerase chain reaction for TBC were initially negative. Despite this, the child was treated with tuberculostatic therapy. TBC was finally confirmed. The child remained on extracorporeal membrane oxygenation for 28 d. Further work-up showed typical lesions of disseminated TBC. The mother was identified as the source of TBC. The boy presents with mild sequelae (fine motor skills). In infants with suspected septicemia, TBC should be considered as differential diagnosis even if the results are initially negative.

Hemodynamic effects of dobutamine and dopexamine after cardiopulmonary bypass in pediatric cardiac surgery.

BACKGROUND: After surgical repair of congenital heart disease, inotropic support is sometimes necessary to wean from cardiopulmonary bypass. In pediatric cardiac surgery, dobutamine and dopamine are often used as inotropic support. Dopexamine is a synthetic catecholamine, which has positive inotropic and vasodilating properties. Because the hemodynamic effects of catecholamines are modified after cardiopulmonary bypass, the aim of this study was to investigate the effects of dobutamine and dopexamine on cardiac index and systemic vascular resistance index after cardiopulmonary bypass in pediatric cardiac surgery. METHODS: The study was performed in a prospective, randomized, and double-blinded cross-over design. The investigation included 11 children for elective, noncomplex congenital heart surgery. After weaning from cardiopulmonary bypass and a 20-min period of steady state, children received either 2.5 microg x kg(-1) x min(-1) dobutamine or 1 microg x kg(-1) x min(-1) dopexamine for 20 min. Cardiac index (transpulmonary thermodilution), mean arterial pressure, central venous pressure, stroke volume, systemic vascular resistance, and central venous oxygen saturation were determined. The primary outcome variable was cardiac index. RESULTS: No difference in cardiac index was observed between the two groups (P = 0.594). Both drugs increased cardiac index, dopexamine from 3.9 +/- 0.6 to 4.7 +/- 0.8 l x min(-1) x m(-2) (P = 0.003) and dobutamine from 4.1 +/- 0.7 to 4.8 +/- 0.7 l x min(-1) x m(-2) (P = 0.004). During treatment with dobutamine, children presented with significantly higher mean arterial pressure (P = 0.003) and systemic vascular resistance index (P = 0.026). CONCLUSIONS: This trial demonstrates that low-dose dobutamine and dopexamine both increase cardiac index during pediatric cardiac surgery but with different hemodynamic effects.

Genetic basis of hypertrophic cardiomyopathy in children.

BACKGROUND: Previous investigations assessing the genetic cause of pediatric hypertrophic cardiomyopathy (HCM) found underlying genetic mutations in 50-60% of cases. The purpose of our study was to analyze whether this number can be augmented by applying next-generation sequencing and directing further diagnostics by discussing unsolved cases in a multidisciplinary board. METHODS AND RESULTS: 42 patients with the diagnoses of HCM made before age 18 years were treated in our center from 2000 to 2016. Genetic analysis was performed in 36 subjects, a genetic defect was detected in 29 (78%) patients. 15 individuals (42%) had pathogenic variants in genes encoding sarcomere proteins, and 5 (14%) in genes coding for components of the RAS/MAPK signaling pathway. 4 subjects (11%) had mutations in the GAA gene (Pompe disease), and 3 (8%) had Frataxin repeat expansions (Friedreich's ataxia). One patient each showed a mutation in BAG3 and LMNA. Discussion of unsolved HCM cases after performing next-generation sequencing (28 genes) in an interdisciplinary board unraveled the genetic cause in 9 subjects (25%). CONCLUSION: A definite genetic diagnosis can be reached in nearly 80% with HCM of childhood onset. Next-generation sequencing in conjunction with a multidisciplinary cooperation can enhance the diagnostic yield substantially. This may be important for risk stratification, treatment planning and genetic counseling.

Transesophageal echocardiography as a guide for patient positioning before neurosurgical procedures in semi-sitting position.

With an incidence of a patent foramen ovale in nearly one fourth of the normal population, neurosurgical procedures in the semi-sitting position are associated with the risk of paradoxical air embolism. The present study was undertaken to evaluate an anesthetic concept to detect a patent foramen ovale with the help of transesophageal echocardiography in anesthetized patients before neurosurgical procedures in the semi-sitting position. Transesophageal echocardiography was performed after induction of anesthesia before surgery to avoid additional physical and psychologic stress for the patients. Thirty-five neurosurgical patients scheduled for elective surgery in the semi-sitting position were examined with help of contrast transesophageal echocardiography. The data of the examined patients were analyzed with respect to efficiency, logistic efforts, and adverse events. Contrast transesophageal echocardiography was combined with a ventilation maneuver to increase right atrial pressure. A patent foramen ovale was detected in 3 of 35 patients. These patients were operated on in a supine position. Oral insertion of the echoprobe was possible in all patients without difficulties. A short-lasting hypertension was observed in 5 patients despite adequate analgesia and sedation. The average time of examination was 25 minutes. None of the patients showed paradoxical air embolism as judged by postoperative neurologic assessment. Contrast transesophageal echocardiography combined with a ventilation maneuver is an effective method in detecting a patent foramen ovale. Moreover, transesophageal echocardiography is a clinical guide to patient positioning. The method of anesthetic management presented to examine anesthetized patients immediately before surgery means less physical and psychologic stress for the patients and causes approximately a 30-minute delay of surgery.

Antiviral Drug-Resistance Typing Reveals Compartmentalization and Dynamics of Acyclovir-Resistant Herpes Simplex Virus Type-2 (HSV-2) in a Case of Neonatal Herpes.

A neonate suffering from herpes simplex virus type 2 disease with central nervous system involvement developed an early recurrence under acyclovir therapy. Isolates from the cerebrospinal fluid and skin lesions were acyclovir resistant, while viruses from blood and trachea were not. Acyclovir combined with foscavir followed by long-term suppressive acyclovir therapy supported normal neurological development.

Analgesia and sedation for painful interventions in children and adolescents.

BACKGROUND: Painful procedures on children and adolescents often have to be performed with the aid of analgesia and sedation in order to prevent pain and emotional distress. Moreover, many procedures can be performed more rapidly and more effectively in a relaxed patient. Because the combination of analgesia and sedation can cause serious or even life-threatening complications, it must be accompanied by the same safety precautions as a general anesthetic. METHODS: Selective review of the literature. RESULTS: A high level of safety can be achieved by adherence to the published guidelines of the societies for anesthesiology and pediatrics. The depth of sedation during procedures performed under combined analgesia and sedation is often equivalent to that resulting from general anesthesia. Therefore, in order to avoid serious complications, combined analgesia and sedation should only be administered by physicians trained in pediatric anesthesia or pediatric critical care. This is particularly so when propofol is used, because it has a narrow therapeutic range and can cause cardiorespiratory respiratory problems without warning. As long as the appropriate safety precautions are followed, non-anesthesiologists can also administer propofol in combination with an analgesic, such as ketamine, to children and adolescents. CONCLUSION: In children and adolescents, the combination of analgesia and sedation can prevent the emotional trauma that would result from a painful procedure, while often enhancing the quality of the procedure itself. This method should be considered a variant of general anesthesia. Accordingly, any non-anesthesiologist employing this method must be as well versed as an anesthesiologist in the management of its specific side effects and complications.

Effect of isoflurane on echocardiographic left-ventricular relaxation indices in patients with diastolic dysfunction due to concentric hypertrophy and ischemic heart disease.

OBJECTIVE: The purpose of this study was to investigate whether isoflurane, a known negative lusitropic agent, exacerbates diastolic dysfunction in patients with preexisting impaired relaxation. DESIGN: Prospective, experimental study. SETTING: Single-institution, university hospital. PARTICIPANTS: Twenty-five patients with diastolic dysfunction due to concentric hypertrophy and ischemic heart disease undergoing elective coronary artery bypass graft surgery. INTERVENTIONS: After approval of the local ethics committee and informed consent, patients randomly received sufentanil/midazolam anesthesia plus either 0.5 to 1.0 minimum alveolar concentration of isoflurane (n = 15) or weight-adjusted boli of urapidil (n = 10) during preparation of the internal mammary artery. Changes in hemodynamic parameters and echocardiographic diastolic indices before and after drug administration were compared. Filling pressures during the study were kept constant within normal range. MEASUREMENTS AND MAIN RESULTS: Hemodynamic changes measured by invasive arterial and pulmonary arterial pressures were comparable between isoflurane and urapidil. Both interventions led to a marked reduction in afterload that was accompanied by a significant increase in thermodilution cardiac output and stroke volume. Transesophageal echocardiographic relaxation indices were also comparable between groups. Transmitral and tissue Doppler E waves increased significantly, leading to larger E/A and Em/Am ratios; whereas the deceleration time and the isovolumetric relaxation time decreased significantly. CONCLUSION: Isoflurane did not exacerbate diastolic dysfunction in patients with concentric hypertrophy and ischemic heart disease. In contrast, isoflurane led to a "normalization" of the relaxation pattern that was attributed to a reduction in left-ventricular loading conditions.