Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor.

Progression of pulmonary hypertension is associated with increased serine elastase activity and the proteinase-dependent deposition of the extracellular matrix smooth muscle cell survival factor tenascin-C (refs. 1,2). Tenascin-C amplifies the response of smooth muscle cells to growth factors, which are also liberated through matrix proteolysis. Recent organ culture studies using hypertrophied rat pulmonary arteries have shown that elastase inhibitors suppress tenascin-C and induce smooth muscle cell apoptosis. This initiates complete regression of the hypertrophied vessel wall by a coordinated loss of cellularity and extracellular matrix. We now report that elastase inhibitors can reverse advanced pulmonary vascular disease produced in rats by injecting monocrotaline, an endothelial toxin. We began oral administration of the peptidyl trifluoromethylketone serine elastase inhibitors M249314 or ZD0892 21 days after injection of monocrotaline. A 1-week treatment resulted in 92% survival, compared with 39% survival in untreated or vehicle-treated rats. Pulmonary artery pressure and muscularization were reduced by myocyte apoptosis and loss of extracellular matrix, specifically elastin and tenascin-C. After 2 weeks, pulmonary artery pressure and structure normalized, and survival was 86%, compared with 0% in untreated or vehicle-treated rats. Although concomitant treatment with various agents can reduce pulmonary hypertension, we have documented complete regression after establishment of malignant monocrotaline-induced disease.

Pulmonary arterial hypertension in children: Diagnostic work-up and challenges.

The diagnostic evaluation of a pediatric patient with suspected pulmonary arterial hypertension (PAH) is extensive but essential, given the rapid progression of the disease if left undiagnosed and untreated. The major goals of performing a complete diagnostic work-up are to confirm the diagnosis of PAH, assess disease severity, rule out associated diseases, and begin to formulate an individualized treatment plan for the pediatric patient with pulmonary hypertension. This article will provide a comprehensive review of the diagnostic work-up of the child with suspected PAH as well as a review of some of the challenges faced when assessing a child for PAH.

Non-congenital heart disease associated pediatric pulmonary arterial hypertension.

Recognition of causes of pulmonary hypertension other than congenital heart disease is increasing in children. Diagnosis and treatment of any underlying cause of pulmonary hypertension is crucial for optimal management of pulmonary hypertension. This article discusses the available knowledge regarding several disorders associated with pulmonary hypertension in children: idiopathic pulmonary arterial hypertension (IPAH), pulmonary capillary hemangiomatosis, pulmonary veno-occlusive disease, hemoglobinopathies, hepatopulmonary syndrome, portopulmonary hypertension and HIV. Three classes of drugs have been extensively studied for the treatment of IPAH in adults: prostanoids (epoprostenol, treprostinil, iloprost, beraprost), endothelin receptor antagonists (bosentan, sitaxsentan, ambrisentan), and phosphodiesterase inhibitors (Sildenafil, tadalafil). These medications have been used in treatment of children with pulmonary arterial hypertension, although randomized clinical trial data is lacking. As pulmonary vasodilator therapy in certain diseases may be associated with adverse outcomes, further study of these medications is needed before widespread use is encouraged.

Nebulized therapies for childhood pulmonary hypertension: an in vitro model.

OBJECTIVES: Sildenafil, tezosentan, and prostacyclin reduce pulmonary vascular pressures in pulmonary hypertension, but have potential to vasodilate the systemic circulation. Nebulized vasodilators allow targeted drug delivery, high local drug concentrations, less systemic hypotension, and better matching of the lung's ventilation and perfusion. We aimed to estimate pulmonary deposition of these drugs from commonly employed nebulizers using in vitro techniques and to create a mathematical model to predict inspired mass of aerosol. DESIGN: Lung deposition was estimated by characterization of drug output and particle size distribution (PSD) of nebulizers using helium-neon laser diffraction techniques. A mathematical model for each device was created to estimate pulmonary deposition using patients' breathing patterns and was verified with a mechanical-breathing model. RESULTS: Total output and PSD were similar for the Hudson Updraft II and Whisperjet nebulizers, consisting of half the nebulizer's charge, with (1/4) of particles < or = 5 microm, in the respirable fraction (RF). Drug output increased with inspiratory flow for the Pari LC Star. Differences were noted in device performance, depending on the drug tested. Estimated pulmonary deposition (mean, 95% CI) was 8.1 (7.2, 9.0)% of the initial drug charge for the Hudson Updraft II, 6.4 (5.8, 7.0)% for the Whisperjet, and 33.0 (28.3, 37.9)% for the Pari LC Star. A mechanical model was consistent with our mathematical model. CONCLUSIONS: All drugs could be nebulized, but expected pulmonary deposition varied depending on the nebulizer and drug.

Haemodynamic characterisation and heart catheterisation complications in children with pulmonary hypertension: Insights from the Global TOPP Registry (tracking outcomes and practice in paediatric pulmonary hypertension).

BACKGROUND: The TOPP Registry has been designed to provide epidemiologic, diagnostic, clinical, and outcome data on children with pulmonary hypertension (PH) confirmed by heart catheterisation (HC). This study aims to identify important characteristics of the haemodynamic profile at diagnosis and HC complications of paediatric patients presenting with PH. METHODS AND RESULTS: HC data sets underwent a blinded review for confirmation of PH (defined as mean pulmonary arterial pressure ≥ 25 mmHg, pulmonary capillary wedge pressure ≤ 12 mmHg and pulmonary vascular resistance index [PVRI] of >3 WU × m(2)). Of 568 patients enrolled, 472 who fulfilled the inclusion criteria and had sufficient data from HC were analysed. A total of 908 diagnostic and follow-up HCs were performed and complications occurred in 5.9% of all HCs including five (0.6%) deaths. General anaesthesia (GA) was used in 53%, and conscious sedation in 47%. Complications at diagnosis were more likely to occur if GA was used (p=0.04) and with higher functional class (p=0.02). Mean cardiac index (CI) was within normal limits at diagnosis when analysed for the entire group (3.7 L/min/m(2); 95% confidence interval 3.4-4.1), as was right atrial pressure despite a severely increased PVRI (16.6 WU × m(2,) 95% confidence interval 15.6-17.76). However, 24% of the patients had a CI of <2.5L/min/m(2) at diagnosis. A progressive increase in PVRI and decrease in CI was observed with age (p<0.001). CONCLUSION: In TOPP, haemodynamic assessment was remarkable for preserved CI in the majority of patients despite severely elevated PVRI. HC-related complication incidence was 5.9%, and was associated with GA and higher functional class.

Presentation and outcomes of ectopia cordis.

BACKGROUND: Ectopia cordis, defined as complete or partial displacement of the heart outside the thoracic cavity, is rare. The cause and pathogenesis are unknown. The anatomy of the heart may be normal, but the presence of structural heart disease as well as noncardiac malformations is common. Patients present incidentally after birth or, more recently, the condition has been diagnosed by prenatal echocardiography. OBJECTIVE: To review the presentation, diagnostic imaging, management and outcomes of infants with ectopia cordis at The Hospital for Sick Children, Toronto, Ontario. METHODS: The medical records of the database of the Division of Cardiology, The Hospital for Sick Children, were searched; echocardiograms, and surgical and autopsy reports were further reviewed. RESULTS: Between 1978 and 1998, 10 patients with ectopia cordis presented to the authors' centre. Normal cardiac anatomy was noted in three, and mild to complex structural cardiac anomalies were noted in the remainder. Associated noncardiac malformations were found in six cases. Six were diagnosed by prenatal ultrasound between 19 and 37 weeks of gestation. Pregnancies were electively terminated or the infants died shortly after birth. Four other neonates with ectopia cordis were referred to the authors' centre. All of these infants subsequently died either at the time of surgery for cardiac and noncardiac anomalies or in the immediate postoperative period. CONCLUSIONS: Despite modern treatment options, the mortality remains high for patients with ectopia cordis, especially in the presence of structural heart disease or other malformations.

[Rhabdomyosarcoma of the orbits in childhood]. / Rhabdomyosarkom der Orbita im Kindesalter.

BACKGROUND: Rhabdomyosarcoma is the most common malignant orbital tumor in children. Treatment modalities (individualized therapy or study protocol) have been changed radically. Surgery was supplemented by radiation therapy and chemotherapy. The objective of our retrospective analysis was to define the prognosis in correlation to changes of treatment in an unselected patient group of a single institution. PATIENTS AND METHODS: Between 1954 and 1995, 18 patients (age at presentation 1 month to 17 years, 11 male and 7 females) with orbital rhabdomyosarcoma were diagnosed and treated at our institution. RESULTS: The 5-year survival rate was 76%. Primary exenteration was replaced by tumor resection (microsurgery), radiation therapy and chemotherapy. Favorable outcome in the precytostatic era (with permanent loss of function) was not significantly improved by polychemotherapy. Microsurgery seems to increase the risk of recurrence. CONCLUSION: Considering the high risk of recurrence, primary exenteration in selected patients with expanded primary tumor is still a therapeutic option.

[ILCOR's new resuscitation guidelines in preterm and term infants: critical discussion and suggestions for implementation]. / Neue Reanimationsrichtlinien der ILCOR bei Früh- und Reifgeborenen: Kritische Diskussion und Vorschläge zur praktischen Umsetzung.

Recommendations of the International Liaison Committee on Resuscitation (ILCOR) become updated every five years with changing evidence resulting in revised recommendations for clinical practice. New data exist concerning the adequate oxygen concentration to be used in the delivery room, the management of imminent meconium aspiration, ventilation strategies and the role of body temperature during and after resuscitation of preterm and term newborn infants. Only in some cases new evidence has led to clear-cut recommendations for or against specific interventions. Therefore the present publication cites the original ILCOR-recommendations and discusses these with regard to their practical implementation. The authors of the present work suggest to commence resuscitation independendly of gestational age with room air and adjust the inspiratory oxygen concentration thereafter on clinical grounds. The authors also advocate the retention of the presently performed intranatal suction procedure in cases of meconium-stained amniotic fluid and the use of therapeutic hypothermia following perinatal asphyxia in term newborns according to the protocol of one of the published randomized, controlled trials. Standard equipment for neonatal resuscitation should include pressure gauge for monitoring of inspiratory pressures, oxygen blender, and pulse oxymeter. The predominant majority of ILCOR-recommendations have only been cited and have been commented with respect to their practical implementation within the clinical context.

Assessment of the relationship between cerebral and splanchnic oxygen saturations measured by near-infrared spectroscopy and direct measurements of systemic haemodynamic variables and oxygen transport after the Norwood procedure.

OBJECTIVES: To evaluate the clinical utility of near-infrared spectroscopic (NIRS) monitoring of cerebral (ScO2) and splanchnic (SsO2) oxygen saturations for estimation of systemic oxygen transport after the Norwood procedure. METHODS: ScO2 and SsO2 were measured with NIRS cerebral and thoracolumbar probes (in humans). Respiratory mass spectrometry was used to measure systemic oxygen consumption (O2). Arterial (SaO2), superior vena caval (SvO2) and pulmonary venous oxygen saturations were measured at 2 to 4 h intervals to derive pulmonary (Qp) and systemic blood flow (Qs), systemic oxygen delivery (DO2) and oxygen extraction ratio (ERO2). Mixed linear regression was used to test correlations. A study of 7 pigs after cardiopulmonary bypass (study 1) was followed by a study of 11 children after the Norwood procedure (study 2). RESULTS: Study 1. ScO2 moderately correlated with SvO2, mean arterial pressure, Qs, DO2 and ERO2 (slope 0.30, 0.64. 2.30, 0.017 and -32.5, p < 0.0001) but not with SaO2, arterial oxygen pressure (PaO2), haemoglobin and O2. Study 2. ScO2 correlated well with SvO2, SaO2, PaO2 and mean arterial pressure (slope 0.43, 0.61, 0.99 and 0.52, p < 0.0001) but not with haemoglobin (slope 0.24, p > 0.05). ScO2 correlated weakly with O2 (slope -0.07, p = 0.05) and moderately with Qs, DO2 and ERO2 (slope 3.2, 0.03, -33.2, p < 0.0001). SsO2 showed similar but weaker correlations. CONCLUSIONS: ScO2 and SsO2 may reflect the influence of haemodynamic variables and oxygen transport after the Norwood procedure. However, the interpretation of NIRS data, in terms of both absolute values and trends, is difficult to rely on clinically.

Neuroblastoma.

Neuroblastoma, a disease primarily of infants and younger children, is a tumor deriving from sympathetic neuroblasts. The variety of tumor location, growth and biologic characteristics represents the clinical manifestations: the range comprises spontaneous regression up to eminently malignant development with resistance to any therapy. Sometimes the tumor is located in the patient's abdomen and becomes important as a differential diagnosis to the urologist. In recent years some important research work has been done, mainly in the field of molecular biology, supporting the hypothesis of two different types of neuroblastoma. Miscellaneous markers and imaging techniques with varying validity are available, but first of all the proof of elevated catecholamines in serum or urine, or the histology of the tumor, ensures the diagnosis. The international consensus for diagnosis, staging and response to treatment is a step of far-reaching significance. The prognosis for most patients, especially for older patients with metastatic disease, remains poor, despite the combination of chemotherapy, radiation therapy and surgery. Further attempts are being made to identify the disease in a localized or early stage with the introduction of screening programs-whereby the benefit of the method is not statistically proven. Treatment trials focus at the moment on autologous peripheral blood cell and bone marrow transplantation.

Paediatric oncology.

Recent research into paediatric urologic oncology has identified a number of certain subgroups of neuroblastoma and Wilms' tumour, which allows a more tailored treatment of the individual child with respect to treatment sequelae and finance issues. The importance of surgery, radiotherapy and cytostatic treatment has to be individualized. The controversies regarding the management of rhabdomyosarcoma of the bladder and the prostate remain unresolved.

Testicular lymphoblastic leukemia/lymphoma.

Acute lymphoblastic leukemia is by far the most frequent malignant disease in children. In all, 5% of the boys affected will develop testicular disease either at initial presentation or during the disease course or as the first site of relapse. Modern treatment regimens have reduced the occurrence of testicular relapses, which was more frequent in the 1970s. There is no place for preventive measures for early recognition of testicular leukemia; routine biopsies have been abandoned, and prophylactic irradiation is not justified. In gross overt disease, orchiectomy is justified (1) in cases of huge bulky testicular disease, (2) if unilateral disease is probable, and (3) if radiation of the testes is refused. In malignant non-Hodgkin's lymphoma, orchiectomy may eventually be the best mode of diagnosing the disease if a boy presents with testicular enlargement. Standard local treatment, however, is irradiation of both testes, if both are affected.

[Neonatal-emergencies: basics in cardiopulmonary resuscitation]. / Neugeborenen-Notfälle: Basale kardiopulmonale Reanimation.

The international guidelines for neonatal resuscitation were recently updated by the American Academy of Pediatrics (AAP), the American Heart Association (AHA) and the International Liaison Committee on Resuscitation (ILCOR). The most important steps in resuscitation of the newly born infant are oxygenation and ventilation, including endotracheal intubation. These fundamental techniques will be emphasized and discussed in a problem-oriented approach. The clinical assessment of the newly born infant is based on a triad of respiration, heart rate and color. If indicated, resuscitation has to be initiated approximately 30 s after birth, i. e. prior to determination of the 1 min. Apgar score and umbilical artery pH. The key to successful neonatal resuscitation is establishment of adequate ventilation; it should commence - after oropharyngeal suctioning and ineffective tactile stimulation - when the heart rate drops < 100 bpm. Clinical evidence supporting the hypothesis that ventilation with room air versus 50 or 100 % oxygen is preferable in terms of neurological outcome is still preliminary and requires further investigation. Chest compressions should be administered if the heart rate remains < 60 bpm (or heart rate 60 to 80 bpm and not rising) despite adequate assisted ventilation. There should be a 3 : 1 ratio of compressions to ventilations to achieve approximately 120 events per minute. Moreover, the international guidelines recommend crystalloid volume expanders (normal saline or Ringer's lactate), red blood cells, sodium bicarbonate and naloxone for cardiopulmonary resuscitation of the newly born infant.

Male fertility in long-term survivors of childhood ALL.

A study of fertility was conducted in postpubertal male patients who had been treated for acute lymphoblastic leukemia (ALL) during childhood or adolescence between 1970 and 1980. Thirteen men (age 18 to 35 years) participated on a volunteer basis. Their age at diagnosis was between 2 and 15 years. Therapy followed the protocol "Memphis VII (Pinkel)." Interview, physical examination, andrological studies (ejaculate), and hormone status (luteinizing hormone, follicle-stimulating hormone, and testosterone) were performed at least 5 years after completion of therapy. No normozoospermia was achieved; 10 patients were identified with asthenozoospermia and 3 patients with azoospermia. With respect to these data, patients treated for ALL between 1970 and 1980 have more significantly impaired spermatogenesis than expected.

Survivors of childhood cancer for more than twenty years.

Present health status, complications, and development of long-term survivors of childhood cancer followed for more than 20 years in a single institution were reviewed. The departmental database was searched to identify patients diagnosed with childhood cancer and consequently treated between 1965 and 1978. A total of 124 (77%) long-term survivors participated on a voluntary basis in the study. A semi-standardized interview consisted of measures evaluating the present health condition, sequelae of treatment, second malignancies, intellectual development and presence of offspring of the former patients. The majority of patients were treated with chemotherapy (82%). 67% received radiotherapy and 67% underwent surgery. A relapse of the primary tumor was diagnosed in four patients as well as a second malignancy in four other patients. In 33% of the long-term survivors one or more serious therapy-related health problems were noted. Adequate mental and intellectual development was achieved in 65%. Children treated in the early years of pediatric oncology seem to have a satisfactory outcome as viewed over the long term. Consequent ongoing follow-up is still necessary to detect health problems and enhance quality of life for subsequent generations of children with cancer.

Cerebral haemorrhage in long-term survivors of childhood acute lymphoblastic leukaemia.

Modern treatment of childhood acute lymphoblastic leukaemia (ALL) has dramatically improved the prognosis for children with this disease. Therapeutic approaches consist of multimodal chemotherapy and radiotherapy with significant long-term side-effects. We report on 4 children out of a group of 120 newly diagnosed patients with ALL, who survived the disease for more than 2 years and developed a cerebral haemorrhage after chemotherapy and fractionated cranial irradiation. Following a period of 2-12 years the four children presented with acute neurological signs and symptoms. i.e. seizures, ataxia and hemiparesis. CT and MRI revealed intracerebral mass lesions, interpreted as haemorrhage. After neurosurgery the patients neurological state improved. Histological examination confirmed the suspected diagnosis of bleeding cavernous haemangioma or capillary telangiectases. There are two possibilities to explain these rare alterations: they may be pre-existent to the disease and therapy or they may be caused by irradiation. CONCLUSION Acute neurological symptoms in patients treated for ALL may be caused by spontaneous cerebral haemorrhaging of cavernous haemangiomas or capillary telangiectases induced by chemotherapy and/or radiotherapy.

[Analysis of paediatric neuro-oncological information on the Internet in German language]. / Analyse pädiatrisch neuro-onkologischer Informationen in deutschsprachigen Internetseiten.

BACKGROUND: The fast growing internet offers easy access to medical information. So far there are limited data concerning the quality of this information. This study examined quality and readability of paediatric neuro-oncological information on the internet in german language. METHOD: Using the search terms "medulloblastoma", "ependymoma", "craniopharyngeoma", "brainstem glioma" and "low grade astrocytoma" in six different search engines, the first 30 universal/uniform resource locators (URLs) of each search engine were assessed. Appropriate Web sites were evaluated in regards to quality using DISCERN-Instrument and checklist rating system. Readability was rated by Flesch Reading Ease score. RESULTS: Out of 889,56 web sites remained evaluable. Most of the sites rated as poor to very poor (49 %), 30 % rated as fair and 21 % as good to very good. Readability was scored as very difficult with complex vocabulary content limiting the usefulness of good web sites. CONCLUSIONS: Search-ing for childhood brain tumours via internet is time consuming and most often ineffective. There is a lack of high-quality and comprehensible information on childhood brain tumours on german web sites. Cooperation of scientific medical societies and the Federal Ministry of Health is essential to provide comprehensible and high-quality information on internet as an effective and supportive resource for patients and their relatives.

Cerebral spinal fluid flow, venous drainage and spinal cord compression in achondroplastic children: impact of magnetic resonance findings for decompressive surgery at the cranio-cervical junction.

UNLABELLED: In order to investigate the diagnostic properties of MRI of the brain and spine in achondroplastic children with regard to decompressive surgery, 25 patients were examined by conventional morphological and by "functional" imaging of CSF flow and magnetic resonance angiography (MRA) of the veins and sinuses at the cranial base following a special protocol. The results were compared to those from age-matched controls and were correlated with each other and retrospectively with the neurological findings. Measurements of distances and angulations at the cranio-cervical junction (CCJ) from MR scans showed similar values to those from conventional radiographs and CTs and thus can be used without correction for spatial distorsion. Signs of cervical medullary compression, myelomalacia and intramedullary cyst formation were found in six, seven and three children respectively. These alterations correlated significantly with each other (P < 0.05). Semiquantitative evaluation of CSF flow demonstrated interruption of CSF pathways at the CCJ, which correlated with CCJ narrowing (P < 0.05). MRA showed a significant narrowing of the jugular foramina with a variable compensatory enlargement of the emissary veins and a significant reduction of the total outflow area (P < 0.01). There were no significant correlations between these MR changes and neurological deficits. CONCLUSION: Due to this unexpectedly poor correlation between magnetic resonance and clinical findings in achondroplastic children, the present role of magnetic resonance in the clinical setting is limited to the demonstration of spinal cord compression in individual cases. In three of our patients with prominent neurological abnormalities, the severe changes demonstrated by magnetic resonance imaging strongly supported the indication for surgical decompression.

Clinical aspects and prognosis of ependymoma in infants and children. A single institution experience.

Thirty-two patients (22 boys and 10 girls) with a histologically confirmed diagnosis of ependymoma were treated between 1972 and 1999. A total macroscopic resection was achieved in 16 of these patients, whereas 15 resections were classified by the surgeon as subtotal. In 1 patient a ventriculostomy was created as part of a palliative strategy. All children over 3 years old were treated with postoperative radiotherapy. Chemotherapy consisted of procarbazine, ifosfamide, etoposide, methotrexate, cisplatin and cytosine arabinoside. There was 1 perioperative death. Twenty children developed a relapse of disease within 2 months to 13 years and 1 month after the initial therapy. A maximal number of five recurrences were seen in 1 patient. The value of adjuvant chemotherapy on the prognosis of children with ependymoma seems to be limited. With regard to the poor outcome, the advisability of further treatment after multiple recurrences is debatable.