Post-mortem analysis of prescription opioids-A follow-up examination by LC-MS/MS with focus on fentanyl.

Our aim was to investigate the reason for relatively low detection rates for opioids and fentanyl in particular in post-mortem cases in the State of Hamburg. We re-analysed 822 blood samples from two different time periods, 2011/12 and 2016. These samples had been previously analysed in accordance with post-mortem routine by a case selected strategy. All samples were re-analysed with an LC-MS/MS method specific for prescription opioids. The main point in the evaluation was to determine whether the previous analysis strategy had led to underreporting of drug-related deaths (DRD), especially with regard to fentanyl. Another aim was to evaluate changes in prescribing prevalence of opiates and opioids. We compared pharmacy claims data in Hamburg with Germany. The analyses showed that the number of DRD remained unaffected by the new analytical strategy. Detection rates in DRD, however, increased for fentanyl 3.4-fold from 1.2% to 4.1%, buprenorphine from 5.9% to 7.6%, oxycodone from 0% to 1.8%, tilidine from 1.8% to 2.4%. The most frequently detected opioids in DRD cases were methadone (39.4%) and heroin (20%). Prescription rates between 2011-2017 decreased in Hamburg for nearly all opioids, morphine by - 43.5%, buprenorphine - 43%, codeine - 57%, fentanyl - 25%, tilidine -17%, tramadol - 31%, and hydromorphone -6%. Oxycodone, tapentadol, and piritramide prescription rates increased. For Germany, a decrease in the prescription rates for fentanyl was also found during this period (-12.9 %), although not as pronounced as in Hamburg. Prescription rates for methadone were three to greater than five times higher in Hamburg as compared to the German average due to the higher number of substituted persons per inhabitant. Conclusion: Despite the global problem of opioid abuse, there are significant regional differences in the nature and extent of opioid abuse. It is necessary to collect data at the national level to develop appropriate prevention strategies.

Difficulties in making the diagnosis of Hirschsprung disease in early infancy.

This study highlights the less common presentations of Hirschsprung disease (HD) and HD-associated enterocolitis (HAE) in neonates and infants. We present three infants whose diagnosis was delayed because of atypical presenting features, especially with failure to gain weight, decreased appetite, episodes of diarrhoea and vomiting and hypoalbuminaemia. The reported incidence of HAE ranges from 0 to 16.2%. To avoid complications of life-threatening HAE, primary care physicians require a high index of suspicion of the more unusual presentations of HD in neonates and infants.

Mediastinal tumors in children: a single institution experience.

Mediastinal masses in children are a heterogeneous group of asymptomatic or potentially life-threatening congenital, infectious, or neoplastic lesions that present complex diagnostic and therapeutic dilemmas. Some patients are asymptomatic; in others, the mass may compress mediastinal structures and cause sudden asphyxia. In these cases, close cooperation is needed among pediatric surgeons, anesthesiologists, intensivists, oncologists, and radiologists. The files of 45 children with mediastinal masses admitted between 1986 and 1999 to the Pediatric Intensive Care Unit (PICU) of Schneider Children's Medical Center of Israel were reviewed. Twenty-one were admitted for perioperative care, and 21 for emergency care, including 19 with respiratory distress. Five of the emergency care group had asphyxia and 10 needed assisted ventilation. Two children were admitted for evaluation and 1 for leukopheresis. The children admitted on an emergency basis had more clinical findings than the postoperative group: almost 80% had dyspnea and more than 45% had oxygen desaturation; 33% had cough and noisy breathing, and 25%, superior vena cava syndrome or hepatosplenomegaly. Eight patients (17.8%) had benign disease and 37 (82.2%) malignant disease. The patients with a benign mass were significantly younger than the patients with a malignant mass (p<0.005); in 5 cases (12.5%), a congenital anomaly presented as a mediastinal mass. Most of the malignant masses were of hematologic origin (40.5%), followed by neurogenic tumors (27%). Twenty-seven patients underwent surgery, including 6 emergency procedures (3 partial resections, 2 biopsies, 1 lymph node biopsy). There were no intraoperative or postoperative deaths. The present series emphasizes the complex care children with a mediastinal mass require. They should be treated in a tertiary center with a multidisciplinary approach.

Blood transfusion practice indicated by paediatric intensive care specialists in response to four clinical scenarios.

OBJECTIVE: Several clinical guidelines exist for blood transfusion in adults but only one refers to children. There are no guidelines for blood transfusion in critically ill children and the paediatric intensive care specialist's approach is unknown. We wished to evaluate the approach toward blood transfusion among a group of paediatric intensive care specialists. METHODS: All certified paediatric intensive care specialists from the Israeli society of pediatric intensive care medicine were requested to complete a questionnaire, which described four hypothetical common scenarios in paediatric intensive care units. In each case, the physicians were asked to denote the haemoglobin threshold at which they would prescribe a blood transfusion and the transfusion volume they would use. The specialists were also asked for their reasons for increasing their haemoglobin threshold for blood transfusion. RESULTS: The questionnaire was posted to twenty six paediatric intensive care specialists, twenty one of whom responded (i.e. 80.8%). There was a wide variation for each scenario in both the suggested haemoglobin thresholds for transfusion (varying by 20-50 g/L) and the transfusion volume (varying by 10-20 mL/kg). The reasons given for increasing their blood transfusion threshold included, in order of importance, shock, haemodynamic instability and hypoxaemia. CONCLUSIONS: There is a marked variability among paediatric intensive care specialists regarding both the threshold haemoglobin level at which blood transfusion is prescribed as well as the volume used.

Benign occipital epilepsy mimicking a catastrophic intracranial event.

OBJECTIVE: To describe the rare, dramatic, presentation of benign occipital epilepsy. METHODS: We describe three children who presented to the pediatric emergency department from 1992 to 1996 with a clinical picture of catastrophic intracranial event. RESULTS: The main signs and symptoms were loss of consciousness in all patients, apnea in two, hemiclonus in two, general hypertonicity in two, eye deviation in two, fixed dilated pupils in one, and decorticate rigidity in two. All underwent emergency intubation, brain scan, and lumbar puncture, and all were treated with antibiotics, in addition to antiviral drugs in two. Two patients were also treated for suspected increased intracranial pressure. Two patients recovered within a few hours and one within 24 hours of admission without any residual neurologic deficit. Electroencephalograms, done within 48 hours after the event, revealed the classic pattern of occipital epilepsy in two patients and bilateral occipital slow wave in one. A 3- to 5-year clinical and electroencephalographic follow-up supported the diagnosis. CONCLUSION: Benign occipital epilepsy in children can mimic a catastrophic intracranial event. Electroencephalography, performed early in the Pediatric Intensive Care Unit, may avoid or shorten unnecessary and aggressive treatments such as hyperventilation, diuretic agents, and prolonged antiviral therapy.

Acute diaphragmatic paralysis caused by chest-tube trauma to phrenic nerve.

A 3 1/2-year-old child developed unilateral diaphragmatic paralysis after chest drain insertion. Plain chest X-ray demonstrated paravertebral positioning of the chest-tube tip, and magnetic resonance imaging revealed hematomas in the region of the chest-tube tip and the phrenic nerve fibers. The trauma to the phrenic nerve was apparently secondary to malposition of the chest tube. This is a rare complication and has been reported mainly in neonates. Radiologists should notify the treating physicians that the correct position of a chest drain tip is at least 2 cm distant from the vertebrae.

Yield of bronchoalveolar lavage in ventilated and non-ventilated children after bone marrow transplantation.

A study was undertaken to retrospectively evaluate the yield of bronchoalveolar lavage (BAL) in a single-institution series of children after bone marrow transplantation (BMT) and to compare the yield of BAL between the ventilated and nonventilated patients. We reviewed charts of 52 consecutive children after BMT who underwent BAL. Thirty patients (41 BALs) were nonventilated (group 1) and 33 patients (45 BALs) were ventilated for respiratory failure (group 2). Eleven patients were included in both groups. BAL was performed a median of 255 and 28.5 days after BMT in groups 1 and 2, respectively (P < 0.001). Group 1:17 pathogens were isolated from 13 BALs; a single pathogen from 10 BALs. Group 2:15 pathogens were isolated from 14 BALs (31.1% positive). Viruses were isolated from 13 BALs in group 2. A severe complication of BAL occurred in only one patient from group 1 (1.1%). Open lung biopsies were performed in one patient in group 1 and eight patients in group 2. The histological findings correlated with the BAL findings in 66.7%. In conclusion, there was no difference in the yield of BAL between the groups. Therapy was changed in one third of the patients dictated by the BAL findings. The risk of severe complications was relatively low. A good correlation between open lung biopsy (OLB) and BAL was found.

Improvement of atypical acute disseminated encephalomyelitis with steroids and intravenous immunoglobulins.

Acute disseminated encephalomyelitis is a demyelinating syndrome that occurs infrequently in children. Various treatment modalities, such as plasmapheresis or steroids or intravenous immunoglobulins (IVIG), have been prescribed. The article describes the results of combined IVIG and high-dose steroids given for 3 days in the treatment of a patient with atypical encephalomyelitis. The results suggest that this approach may be more beneficial than the application of either drug alone.

Severe allergic bronchopulmonary aspergillosis in an infant with cystic fibrosis and her asthmatic father.

An infant with cystic fibrosis and her asthmatic father were diagnosed as suffering from allergic bronchopulmonary aspergillosis (ABPA). Cystic fibrosis was diagnosed in the infant at 6 weeks of age, and gene mutations were W1282X/G542X. She was diagnosed definitively as suffering from ABPA at age 3.5 years, but had suggestive symptoms from age 11 months. This may be the youngest age described to date for ABPA. The child responded well to systemic steroid therapy, but remained steroid-dependent over the next 4 years. Treatment with itraconazole enabled a marked reduction in steroid dosage. The father was an asthmatic, and a heterozygote for the cystic fibrosis transmembrane regulator (CFTR) mutation W1282X. He had a normal sweat test, atopy, and moderate reversible airway obstruction. There was no proven exposure to Aspergillus in the home environment. The importance of considering the diagnosis of ABPA even in infancy, the therapeutic dilemmas, and the possible role of abnormal CFTR function in the development of ABPA are discussed.

Hemophagocytic lymphohistiocytic syndrome: Unrecognized cause of multiple organ failure.

OBJECTIVE: To describe an often-unrecognized clinical picture of multiple organ failure in hemophagocytic lymphohistiocytic syndrome (HLS). DESIGN: Retrospective chart review. SETTING: A ten-bed pediatric intensive care unit (PICU) in a tertiary children's university hospital. PATIENTS: A total of 11 children (age, 5 months to 13 yrs) who fulfilled the criteria for the diagnosis of familial- or infectious-associated hemophagocytic lymphohistiocytosis and who required intensive care support for organ failure. INTERVENTION: None. MAIN RESULTS: During a 10-yr period, 5,439 children were hospitalized in our PICU. A total of 11 children were diagnosed as suffering with HLS. Of these 11 patients, three (27%) had the familial form and eight had the infectious-associated form. After admission to the PICU, seven patients (63%) were diagnosed as suffering with HLS and each had one or more organ failures (patients 3-7, 9, and 10). All presented with fever, hepatomegaly, and splenomegaly; in addition, all had at least two of the following: anemia, neutropenia, or thrombocytopenia. All 11 had lymphohistiocytic accumulation in bone marrow (n = 10), lymph node (n = 2), lung (n = 2), and/or liver (n = 1). Organ failure was noted most often in the respiratory system (n = 7) attributable to severe, acute respiratory distress syndrome and pleural effusion. Of the 11 patients, six had cardiovascular involvement that manifested as shock in three and as capillary leak syndrome in three. Renal failure occurred in four patients. Of these, two required hemodiafiltration and one required peritoneal dialysis. Liver failure occurred in three and central nervous system involvement and coma in three. Most of the patients required massive therapeutic intervention, including assisted ventilation (n = 6), inotropic support (n = 3), and hemofiltration (n = 3). A total of seven patients (63%) died. CONCLUSIONS: Hemophagocytic lymphohistiocytic syndrome in the pediatric population may have a dramatic clinical picture, with multiple organ failure as a presenting symptom or early in the disease course, mandating intensive support in the PICU.

World Health organization (WHO) and the World Heart Federation (WHF) pathobiological determinants of atherosclerosis in youth study (WHO/WHF PBDAY Study) 1986-1996. Histomorphometry and histochemistry of atherosclerotic lesions in coronary arteries and the aorta in a young population.

BACKGROUND AND AIM: The present work is a chapter in an investigation directed by the World Health Organization on the Pathobiological Determinants of Atherosclerosis In Youth (WHO-PBDAY). Our aim was to study the development of atherosclerotic lesions in a young population. METHODS AND RESULTS: Samples of left anterior descending coronary artery (LDC) and thoracic (TA) and abdominal aorta (AA) from five Collaborating Centres (Budapest/Hungary, Havana/Cuba, Heidelberg/Germany, Mexico City/Mexico, Peradeniya/Sri Lanka) of 214 subjects who died aged 15 and 34 were analysed at the Budapest Reference Centre. Slides stained with haematoxylin-eosin and with stains for extracellular matrix were quantitatively and qualitatively evaluated. Mean intima/media (I/M) ratio and the prevalence of type III-IV lesions (preatheroma; atheroma; calcified and fibrous atheroma) were determined and compared in different risk factor (high blood pressure, smoking) groups. High I/M ratio was found in the LDC and type III-IV lesions were frequently found both in the LDC and in the AA. I/M ratio and the occurrence of type III-IV lesions increased in all arteries by age. Atherosclerotic lesions in men were more severe, particularly in the LDC. Geographic origin had a limited effect on the histologic lesion parameters. Appearance of type III-IV lesions was associated with substantially different extracellular matrix changes. Myoelastic layer formation was found in each artery in both early and type III-IV lesions. Hypertension was associated with higher prevalence of type III-IV lesions in all arteries, in particular, in the TA; smoking showed a significant effect on the AA only. CONCLUSIONS: Atherosclerotic lesions were found in many of these young subjects. The effect of hypertension and smoking on their development suggests that control of risk factors, beginning in early adolescence, could help to prevent cardiovascular diseases.

Open lung biopsy--successful diagnostic tool with therapeutic implication in the critically ill paediatric population.

Open lung biopsy (OLB) is an important diagnostic tool in children with immune deficiency and/or chronic lung disease with diffuse pulmonary compromise. These patients require a tailored therapeutic approach owing to their fragile status and the side effects of unnecessary or inadequate treatment. Twenty-six patients of mean age 5.6 y underwent 41 open lung biopsies in our centre between 1991 and 1995. Seventeen (65%) were immunocompromised (including 13 with malignancy) and 9 had other lung diseases. The biopsies were diagnostic in 25 patients (96%), and complete clinical-pathological correlation was found in 11 (42%). A specific infectious aetiology was detected in nine patients (35%), all of them immunocompromised. Therapeutic changes were instituted on the basis of the biopsy findings in 18 patients (69%). Two patients had postoperative complications (prolonged pleural leak). We conclude that OLB is a safe diagnostic procedure even in the critically ill child and should be employed without hesitation when conventional methods fail to provide a definitive diagnosis to help redirect therapy.

Early emergence of ganciclovir-resistant human cytomegalovirus strains in children with primary combined immunodeficiency.

Children with primary combined immunodeficiency (CID) and human cytomegalovirus (HCMV) infection often deteriorate despite antiviral therapy. In this study, the emergence of ganciclovir-resistant strains was examined in 6 children with CID and HCMV infection, using sequence analysis of the HCMV UL97 gene and virus susceptibility assays. Mutations in the proposed ATP binding site associated with ganciclovir resistance were found in 4 of the 6 children. In 1 patient with B severe CID, an unusual multiplicity of mutations was found in the UL97 substrate binding domain between aa 590-606. All mutations were detected within 10 days to 3 weeks from initiation of therapy. The emergence of resistant strains in children with CID appears earlier than in other groups of HCMV-infected patients. These findings may have relevance to the cellular pathways involved in viral DNA repair and mutagenesis, and they indicate the need for early and frequent genotypic monitoring and prompt therapeutic modification in this patient population.

Prolonged croup due to herpes simplex virus infection.

UNLABELLED: Herpes simplex virus (HSV) is an uncommon cause of acute laryngitis in immunocompetent patients since it mostly occurs in immunocompromised subjects. We present two previously healthy children with prolonged gingivostomatitis and stridor (lasting 3 and 4 weeks) in whom HSV-1 was isolated from subglottal ulcers. CONCLUSION: HSV should be considered a possible pathogen in cases of prolonged or atypical croup not only in immunocompromised or elderly patients but also in otherwise healthy children.

Screening obstructive sleep apnoea syndrome by home videotape recording in children.

Overnight polysomnography (PSG) has been used to diagnose and assess the severity of obstructive sleep apnoea syndrome (OSAS) in children. The aim of this study was to determine whether home video-recording of children during sleep may be used for screening OSAS. In 58 children suspected of having OSAS, PSG results were compared with the corresponding analyses of 30 min video-recordings of each child sleeping at home. The video-recordings were evaluated by: 1) overall investigator's clinical judgement; and 2) a scoring system based on noisy breathing, movements, walking episodes, apnoea, chest retractions and mouth breathing. PSG results were highly correlated with the video test results, with agreement in 49 out of 58 (84%). In 36 of the 58 children, the PSG was abnormal compared with 41 out of 58 abnormal video tests. The sensitivity of the overall investigator judgement of video test was 94% (34 out of 36) and the specificity 68% (15 out of 22). Video scores > 10 were highly predictive of OSAS, whilst scores < 5 were associated with normality. Using a stepwise logistic regression analysis, each of the scoring variables was tested against the PSG results and an equation was formulated for predicting PSG by the video test. The equation predicted PSG results in 49 out of 58 (84%) cases. Thirty minutes of home video-recordings during sleep is a reliable screening method for obstructive sleep apnoea syndrome in children. This technique may, thus, improve patient selection for polysomnography.

Sudden infant death syndrome in the Tel Aviv and Petah Tikva districts.

We studied the epidemiology and incidence of the sudden infant death syndrome (SIDS) in the Tel Aviv and Petah Tikva districts during the period April 1980 to March 1983. Sixty-nine infants were diagnosed as SIDS and 38 of them had autopsies. Four cases were excluded because their autopsy revealed other diagnoses. When calculating for 24,183 live births per year during the study period, the rate of SIDS was found to be 0.47-0.90:1,000 live births. Other epidemiologic characteristics were: female:male [corrected] ratio 1:1.3; peak incidence at 2-4 months age, with 80% before age 6 months; increased incidence during the autumn and winter months (85% of SIDS cases); and highest incidence between midnight and 8:00 AM (84% of SIDS cases). None of the infants had a history of a previous apparent life-threatening event. Birthweight of infants who died of SIDS was not significantly different from that in the general population. No statistical relation to DTP (diphtheria, tetanus, pertussis) vaccination was found. Half the cases had mild respiratory illness during the week that preceded the sudden death. The incidence of parental cigarette smoking was higher than in the general population (56.5% vs. 36-53%; P less than 0.005) as well as the incidence of maternal smoking during pregnancy. We conclude that the incidence of SIDS in Israel is relatively low. The epidemiologic characteristics of SIDS in Israel are very similar to the presentation of the syndrome in other countries.