[Complicating neonatal Escherichia coli meningitis]. / Subdurale gekammerte Abszesse nach neonataler Colimeningitis - Fallbericht über eine erfolgreiche konservative Therapie -

Neonatal Escherichia coli meningitis is a serious disease with high mortality and poor outcome. Ventriculitis, brain abscess and subdural empyema are frequent, with no homogeneous recommendations available for these complications. The case of a newborn infant who developed sepsis and meningitis caused by E. coli is presented. During intravenous treatment with ampicillin, cefotaxime and gentamycin in recommended doses, the patient developed severe subdural abscesses detected on MRI. After consequent antibiotic therapy over 2 months with fosfomycin, amikacin and meropenem the patient improved clinically and the abscesses regressed and disappeared without neurosurgical intervention. At the age of 6.5 months the infant is healthy and well developed. The conservative treatment of subdural abscesses complicating neonatal Escherichia coli meningitis without neurosurgical intervention is possible. The treatment of the individual case should be discussed between pediatrician and neurosurgeon.

First experience with basiliximab in pediatric liver graft recipients.

Several studies have shown a significant reduction of acute cellular graft rejection in adult liver and kidney graft recipients treated with monoclonal anti-interleukin-2 (IL-2)-receptor antibodies. The mechanism was inhibition of activated T-helper cells by blocking the alpha-chain (CD25) of the IL-2 receptor. The pilot study described here evaluated the use of basiliximab in pediatric liver transplantation (LTx), which is the first report on its use in children. Fifty-two liver-transplanted children were analyzed in this study. A matched-pair historical control group (n = 26) received cyclosporin A (CsA) and prednisolone, and patients in the basiliximab group (n = 26) were treated with low-dose CsA and basiliximab (after reperfusion and on day 4 post-transplant). The incidences were compared of acute graft rejections, infectious complications, and the adverse effects of immunosuppressive medication within the first 6 months post-transplant. The incidence of acute rejection was significantly higher in the control group (61.5% vs. 11.5%, p = 0.0004). The frequency of infectious complications was similar (46.1% vs. 53.8%). Patients in the basiliximab group showed less arterial hypertension; however, the differences were not statistically significant (30.7% vs. 7.7%, p = 0.07). Nephrotoxicity, hepatotoxicity or neurotoxicity were only seen in the control group (7.7%; 3.8%; 3.8%, respectively). Hence, the use of basiliximab in combination with CsA and steroids in pediatric liver transplant recipients is safe and reduces the incidence of acute graft rejection. Further studies are needed to confirm our preliminary results and to analyze long-term effects on post-transplant lymphoproliferative disease, chronic rejection, and patient survival.

Intensive care management after pediatric liver transplantation: a single-center experience.

A retrospective study was conducted to determine the significance of intensive care management on outcome after liver transplantation (LTx) in children. Of 195 transplants performed in 162 children, factors affecting morbidity and mortality were documented during the post-operative intensive care unit (ICU) stay. To assess the gain in experience of ICU management, we compared mean ventilation time and stay in the ICU as well as mortality, incidence of surgical complications, infections, and rejection episodes, during three different time-periods (October 1991-August 1994, September 1994-July 1996, and August 1996-February 1998). The time spent by patients in the ICU (9.7 days vs. 7.9 days vs. 4.7 days, p < 0.001) and time on ventilation (5.2 days vs. 3.1 days vs. 1.2 days, p < 0.001) were significantly reduced over the duration of the study. The overall mortality was 18.0% (n = 30) and 76.7% (n = 23) of these deaths occurred during the early post-operative period in the ICU. The incidence of severe surgical complications decreased significantly over time, and the application of intra-operative Doppler ultrasound since 1994 led to detection of 27 correctable vascular complications. The overall incidence of acute cellular rejection episodes in our center was 64.1%: 43.5% of the infectious episodes occurred in the ICU (bacterial 70.2%, viral 12.3%, and fungal 17.5%). The main side-effect from immunosuppressive drugs was arterial hypertension in 29% of the patients. We conclude that our efforts to improve intensive care management and monitoring were the key elements in reducing morbidity and mortality after pediatric LTx.

Interleukin-1 receptor antagonist in ascites indicates acute graft rejection after pediatric liver transplantation.

Acute graft rejection is one of the most frequent complications after pediatric liver transplantation (LTx). In clinical practice, it is sometimes difficult to differentiate acute cellular graft rejection from other complications because clinical and chemical findings are often nonspecific. We therefore investigated the value of cytokine quantification in drained ascites, in addition to quantification of cytokine concentrations of serum, in 30 children in the first 2 weeks after orthotopic liver transplantation (OLT). Six of 30 patients showed acute graft rejection, with rising levels of alanine aminotransferase (ALT) and alpha-glutathione-S-transferase (alpha-GST) in serum up to 24 h prior to biopsy-proven rejection. There were no significant elevations of interleukin-2 receptor (IL-2r) and interleukin-6 (IL-6) in serum and ascites. In contrast to these findings, the concentration in ascites of the interleukin-1 receptor antagonist (IL-1ra) increased 48 h before rejection was proven by liver biopsy (p < 0.01, in comparison with the non-rejecting group, n = 24). The IL-1ra concentration in ascites was up to 11-fold higher than in serum during rejection (15.43 vs. 1.38 ng/mL). Two children with early infectious complication showed no significant increase in ascitic IL-1ra concentration. We conclude from these data that quantification of IL-1ra in ascites indicates the start of graft rejection after LTx. As long as abdominal drainage is performed, this non-invasive procedure may be of additional value in differential diagnoses and early diagnosis of rejection.

Improved outcome in haemophagocytic lymphohistiocytosis after bone marrow transplantation from related and unrelated donors: a single-centre experience of 12 patients.

Haemophagocytic lymphohistiocytosis (HLH) is an autosomal recessive disease with histiocytic and lymphocytic infiltrations in multiple organs. Cure seems possible only by allogeneic bone marrow transplantation (BMT), but matched sibling donors (MSD) are restricted and high mortality rates are associated with BMT from unrelated donors (URD). We report on 12 consecutive HLH patients with an improved outcome following URD transplants. Eight patients received BMT from URD, four from MSD. Five patients had signs of active HLH at the time of BMT. The conditioning regimen consisted of 20 mg/kg busulphan, 60 mg/kg VP-16 and 120 mg/kg cyclophosphamide and, in case of URD, 90 mg/kg antithymocyte globulin. The doses of busulphan and VP-16 were reduced during the programme to 16 mg/kg and 30 mg/kg, respectively. Using a fivefold graft-versus-host disease (GVHD) prophylaxis, GVHD was absent or mild in 10, and moderate or severe in two patients undergoing unrelated transplants. One patient with URD experienced graft failure and was retransplanted on day 37. Major toxicities were hepatic veno-occlusive disease in five, capillary leak syndrome in two, pneumonia in three, sepsis in one, severe mucositis in one and seizures in two patients. All patients are alive without HLH after a median follow-up of 24.5 months. One patient has chronic GVHD, another patient has severe retardation. Three patients show slight to moderate development delay. These results indicate that in HLH, BMT from matched unrelated donors should be performed. Incomplete resolution of disease activity need not impede a successful outcome.

Monitoring erythrocyte free radical resistance in neonatal blood microsamples using a peroxyl radical-mediated haemolysis test.

Inadequate resistance to oxidative stress has been implicated in several diseases of premature children. Antioxidative defences at the membrane level can be studied by measuring haemolysis induced through exposure of erythrocytes to the free radical generator AAPH (2,2'-azobis (2-amidinopropane)dihydrochloride). We developed a micromodification of this haemolysis test requiring only 15 microl of erythrocytes derived from capillary blood samples. The time needed for 50% haemolysis (T50%) was used to characterize radical resistance of erythrocytes. T50% results in adult samples were highly reproducible. T50% values in healthy term infants on the first 2 d of life were lower than in adults (p < 0.001), but increased to the same level thereafter. A correlation was found between T50% values and plasma tocopherol levels as determined in plasma of each of the capillary blood samples (p < 0.001). On the first day of life T50% results in preterm infants (n = 20) were higher than in term infants (p < 0.001). It was easy to monitor T50% results and plasma tocopherol levels in preterm infants that were not at all burdened by the sampling method, almost daily over several weeks. The micromodification presented simplifies monitoring of antioxidative defences in sick preterm infants.

Monoclonal antibodies for the detection of desialylation of erythrocyte membranes during haemolytic disease and haemolytic uraemic syndrome caused by the in vivo action of microbial neuraminidase.

Especially in childhood, the in vivo action of microbial neuraminidase may cause haemolytic anaemia or life-threatening haemolytic uraemic syndrome. The exposure of the Thomsen-Friedenreich (T) crypto-antigen and T-antigen polyagglutinability of erythrocytes has been described as the first sign of toxic cleavage of N-acetylneuraminic acid (Neu5Ac) from sialoglycoproteins of cell membranes. This phenomenon may, however, be too unspecific to initiate treatment for toxin elimination. The present study investigated the diagnostic effectiveness of a panel of three monoclonal antibodies (mcabs) for the estimation of the clinical significance of neuraminidase action in vivo. Depending on the amount of Neu5Ac released, the mcabs I-C4, II-Q9 and III-Y12 recognized different epitopes on erythrocyte asialoglycophorin. In 1345 patients, the mcab II-09 detected cleavage of Neu5Ac in 32 children who had T-antigen polyagglutinability and mild to moderate haemolytic anaemia. However, only 10 patients, whose erythrocytes were agglutinated by the mcabs III-Y12 or I-C4, developed severe haemolysis, thrombocytopenia, and finally the life-threatening haemolytic uraemic syndrome (p<0.0002). In conclusion, these mcabs provided an early marker of the in vivo action of neuraminidase. Two different degrees of erythrocyte desialylation, as defined by these mcabs, are suggested to reflect the severity of toxin-associated disease.

Melatonin and 6-hydroxymelatonin sulfate excretion is inversely correlated with gonadal development in children.

To delineate the development of melatonin (MLT) production during childhood, we measured the excretion of MLT and 6-hydroxymelatonin sulfate (MLTS) in the urine of children (n = 134) from the 26th week of gestation until the age of 20 years. MLTS excretion showed a diphasic pattern with declining values in preterm babies with lowest values around term. After birth, the values remained low for the first 6 months of life. The highest values were reached between 4 and 7 years of age with a smooth but steady decline thereafter. A night-day difference was not detectable before the age of 6 months; the greatest night-day variations occurred at the time of the highest MLTS excretions. The MLT values showed an identical pattern but with amounts 1,000 times smaller; the ratio of MLTS to MLT increased from 40:1 in preterm babies to 900:1 in prepubertal children. In summary, the MLT/MLTS excretion exhibits the highest activity with respect to total secretory capacities as well as night-day differences at the time of gonadal quiescence during childhood. The strong inverse correlation of MLT and MLTS excretion with the hypothalamic-pituitary-gonadal activity points to a causal relationship between pineal gland activity and pubertal development.

Decreasing melatonin and 6-hydroxymelatonin sulfate excretion with advancing gestational age in preterm and term newborn male infants.

We investigated the ontogeny of melatonin synthesis during fetal maturation by measuring the melatonin (MLT) and 6-hydroxymelatonin sulfate (MLTS) excretion in the urine of male infants aged 2-7 days and gestational age 26-42 weeks. We found a negative correlation between advancing gestational age and the MLT and MLTS excretion expressed as total 24-h amount, ratio of 24-h amount to creatinine and ratio of 24-h amount to body surface area. The ratio of MLT to MLTS was found to be about ten times higher in the study group than in prepubertal children, which might reflect the immaturity of hepatic sulfation capacities. The total amount of excreted MLT and MLTS was only one-tenth the prepubertal values. No day/night differences in MLT and MLTS excretion could be detected. We conclude that the fetal pineal gland is capable of a limited melatonin synthesis from the 26th week of gestation onwards, with decreasing values reaching its nadir around term. This indicates that the amount of fetal MLT excretion is not determined by synthesizing capacities of the pineal gland but by the development of neural connections to the pineal gland.

Effective treatment of acute hyperkalaemia in childhood by short-term infusion of salbutamol.

UNLABELLED: Hyperkalaemia is a life-threatening emergency and infusion of glucose with insulin has so far been regarded as the standard treatment of choice. Recently the beta-2 stimulatory drug salbutamol has been shown to be an effective agent to treat hyperkalaemia by inducing a shift of potassium into the intracellular compartment. We treated 15 children aged 0.1-14 (mean 5.2) years suffering from acute hyperkalaemia (mean level 6.6 +/- 0.54, range 5.9-7.7 mmol/l) with a single infusion of salbutamol (5 micrograms/kg over 15 min). Serum potassium concentrations decreased significantly within 30 min to levels of 5.74 +/- 0.53 and 4.92 +/- 0.53 mmol/l after 120 min (P < 0.001, respectively). No side-effects occurred other than a light increase in heart rate in 3 patients. CONCLUSION: A single intravenous infusion of salbutamol at a dose of 5 micrograms/kg is a highly effective treatment for hyperkalaemia with minimal clinical side-effects. The effect lasts for at least 120 min and may reverse hyperkalaemia in some patients without further interventions so that salbutamol seems justified as the first choice treatment for this condition in childhood.

Low birthweight in Germany 1990-92.

The reunification in 1990 of the German Democratic Republic (GDR) and the Federal Republic of Germany (FRG) produced profound social transformations. Changes in the distribution of low birthweight (LBW, < 2500 g) in the two parts of the country between 1990 and 1992 have been studied by analysing vital statistics for the period. In absolute numbers, livebirths in the former FRG remained stable, while those in the former GDR declined by 51%. Numbers of LBW livebirths increased slightly in the former FRG and decreased in the former GDR; those in the category between 500 and 999 g remained stable in the former GDR and increased in the former FRG. However in terms of proportion, livebirths in this category doubled in the former GDR. Migration rates for the same period showed a shifting population from East to West particularly of young people, and maternal age-specific numbers of livebirths decreased in both countries. Psychosocial stress may have contributed to the rise in ELBW, but it is also possible that the improvement and sharing of perinatal management strategies may have led to increased survival of babies < 1000 g. Most importantly, the observed rise in the proportion of ELBW births (except those < 500 g) could be a result of the introduction of the more comprehensive definition of livebirth into the former GDR.

Living donor for liver transplantation.

Since living related liver transplantation was first performed in 1989, more than 150 cases have been performed worldwide, mostly in the United States and Japan. This paper reports the first series of living related liver transplantation in Europe. Twenty living related liver transplantation surgeries were performed over a 13-mo period, with an overall patient survival of 85%. For patients who underwent elective transplantation (n = 13), the survival rate was 100%. Technical complications included one arterial thrombosis necessitating retransplantation and five bile leaks requiring surgical revision. The technical improvements that permit avoidance of these complications are discussed. A detailed description of the living related liver procurement is given. All procurements yielded grafts of excellent quality. No intraoperative complications occurred, and no reoperations were necessary. No heterologous blood transfusion was needed. In two patients, incisional hernias developed after wound infection. Living related liver transplantation does not absolve the transplant community of efforts to promote cadaveric organ procurement. Nevertheless, living related liver transplantation does have the advantage of a readily available graft of excellent quality, permitting transplantation with optimal timing under elective conditions. Several centers are now preparing living related segmental liver transplants, following the model of our protocol, for three reasons: (a) to obtain superior results compared with cadaveric liver transplantation; (b) to overcome cadaveric organ shortage and further reduce pretransplantation mortality and (c) to provide viable organs in countries where cadaveric organ procurement is not established. When performed by a team experienced in pediatric liver transplantation and in adult liver resection, living related liver transplantation is an excellent modality for the treatment of end-stage liver disease in children.

High-dose versus low-dose bovine surfactant treatment in very premature infants.

The aim of the study was to determine if high-dose bovine surfactant (Alveofact, initially 100 mg/kg birth weight) would improve oxygenation compared with low-dose surfactant (50 mg/kg birth weight) administered intratracheally within 1 h after birth. Inclusion criteria included gestational age 24-29 weeks and birth weight 500-1500 g, intubation and mechanical ventilation, absence of congenital malformations and bacterial infections. Retreatment was considered if the fraction of inspired oxygen (FiO2) was > 0.4 (dose 50 mg/kg birth weight). The primary endpoint was level of oxygenation (PaO2/FiO2) 2 h after treatment. The study design was a sequential analysis using a triangular test with alpha = 0.05 and 95% power to detect a 25% improvement in the endpoint. Oxygenation was improved significantly with high-dose (n = 42) compared to low-dose treatment (n = 48): 30.9 +/- 15.0 kPa (231.5 +/- 112.7 mmHg) versus 24.1 +/- 15.7 kPa (180.6 +/- 118.0 mmHg) (mean +/- SD). The survival rate was 83% in both groups and the incidence of pulmonary interstitial emphysema was 33% versus 14% with the high-dose treatment. We conclude that high-dose surfactant significantly improved oxygenation and reduced lung barotrauma. An initial dose greater than 50 mg/kg birth weight of surfactant is required for optimal acute response.

The acute infection-associated hemolytic anemia of childhood: immunofluorescent detection of microbial antigens altering the erythrocyte membrane.

The majority of acute infection-associated hemolytic diseases of infancy and childhood have been suggested to be caused by exogenic alterations of the erythrocyte surface, though laboratory methods for their further evaluation were not yet available. Investigating 96 children, the present study characterizes 72% of cases as corresponding to this type of acute acquired hemolytic anemia, which cannot be clearly related to autoantibodies against unmodified components of the host's own red cells. Using a new immunofluorescence test, the erythrocyte membrane of 80% of these children was found to be altered in vivo by nonspecific adsorption of foreign material released from the infectious micro-organisms. In 24% of cases additive binding of complement was detectable by an antiglobulin test. Thus, the adsorption of microbial antigens to the red cell surface is suggested to be one of the causes for the removal of altered erythrocytes due to phagocytosis or a complement-dependent destruction during the course of infection-associated hemolytic anemia. Especially in childhood, the immunofluorescent detection of an erythrocyte sensitization in vivo provides a further characterization of this type of mostly transient hemolytic disease, which probably can be treated without any immunosuppressive drug, merely by elimination of the underlying infection.

Early treatment of respiratory distress syndrome with bovine surfactant in very preterm infants: a multicenter controlled clinical trial.

OBJECTIVE: To determine the effect of bovine surfactant (SF-RI 1, Alveofact) administered during the first hour following birth to very premature infants [gestational age (GA), 25-30 weeks] in a multicenter, controlled trial. HYPOTHESIS: Survival without bronchopulmonary dysplasia (BPD; definition: ventilator dependency or FiO2 greater than 0.3 during spontaneous respiration) at day 28 is increased in surfactant-treated infants (sequential analysis). PATIENTS AND METHODS: Thirty-four infants [GA 28.0 +/- 1.5 SD weeks, birth weight (BW), 1,048 +/- 299 g] received 50 mg/kg BW surfactant, whereas 35 infants (GA, 27.6 +/- 1.5 weeks, BW 969 +/- 269 g) served as controls. Retreatment with surfactant (up to three identical doses) 12-24 hours after the previous dose was permitted if FiO2 was greater than 0.5. RESULTS: Survival without BPD was significantly higher in surfactant treated infants (26/34) compared to controls (14/35; P = 0.003), but in the incidence of pulmonary air leaks, patent ductus arteriosus, intracranial hemorrhage, and nosocomial infections they were not different. CONCLUSION: Bovine surfactant treatment improves survival without BPD in very premature infants at risk for neonatal respiratory distress syndrome (RDS).

[The effect of bovine surfactant in premature infants with respiratory distress syndrome. Results of an open, multicenter study]. / Die Wirkung eines bovinen Surfactant bei Frühgeborenen mit Atemnotsyndrom. Daten einer offenen, multizentrischen Studie.

We investigated the effects of a bovine surfactant (SF-RI 1, Alveofact) in very low birth weight infants (VLBW, b.w. 500-1500 g) with established respiratory distress syndrome (RDS; definition: FiO2 greater than or equal to 0.6 or peak inspiratory pressure greater than 22-28 cm H2O). Fifty mg/kg b.w. bovine surfactant was administered intratracheally as a bolus, if the acute response was unsatisfactory (FiO2 greater than 0.5), further administrations of surfactant up to a maximum cumulative dose of 200 mg/kg b.w. were permitted. One hundred and sixty-four VLBW infants (gestational age 28.0 +/- 2 wks; b.w. 1054 +/- 251 g; mean +/- SD) with a mean FiO2 of 0.84 +/- 0.15 were enrolled in the study. Maximum improvement in oxygen requirements was observed 1/2 h post administration (FiO2 0.53 +/- 0.22); incidence of complications during the neonatal period: pulmonary interstitial emphysema 26%, pneumothorax 10%, patent ductus arteriosus 37%, intracranial hemorrhage 47%. The overall survival rate was 61%, survival rate without bronchopulmonary dysplasia (BPD) was 47%. A multiple regression analysis was performed in order to identity factors determining survival without BPD (p less than or equal to 0.05). We observed a positive correlation for gestational age and birth weight and a negative correlation for pretreatment oxygen requirements. For further optimizing surfactant-therapy in VLBW infants with RDS, studies are mandatory using intervention criteria at lower FiO2-values and higher initial doses of bovine surfactant.

Does prophylactic use of bovine surfactant change drug utilization in very premature infants during neonatal period?

The efficacy of a bovine surfactant preparation (SF-RI 1) to increase survival without bronchopulmonary dysplasia (BPD) was studied in very premature infants in a multicenter, randomized sequential trial. Thirty-four infants were randomized to surfactant treatment, whereas 35 infants served as controls. As part of the study, pharmacotherapy with antibiotics, sedatives, catecholamines, diuretics, methylxanthines, mucolytics, muscle relaxants, digoxin, and indomethacin was registered during week 1 and weeks 2-4. As to the endpoint of the study a significantly increased survival rate without BPD was observed in surfactant-treated infants (76%) compared to controls (40%). Significant differences concerning drug utilization were found through week 1 with increased use of methylxanthines in surfactant-treated infants, which persisted during weeks 2-4 as well as a reduced incidence of diuretic therapy in surfactant-treated infants during weeks 2-4. These differences may be attributed to the shorter interval of mechanical ventilation in surfactant-treated infants (11 days) compared to controls (27 days), and to the above mentioned increased survival rate without BPD.

Drug utilization in very premature infants in neonatal intensive care units.

Neonatal drug utilization in very premature infants (gestational age (GA) 24-29 weeks), requiring intubation and mechanical ventilation at birth was registered as part of a multicenter controlled clinical trial of high-dose versus low-dose bovine surfactant (initial doses 100 mg/kg birth weight (b.w.) versus 50 mg/kg b.w.). Drug utilization during 4 weeks after birth was analyzed in 164 infants (mean GA 27.2 +/- 1.2 (SD) weeks, b.w. 970 +/- 145 g (SD)). More than half of the study infants received antibiotics (98.8%), sedatives and analgesics (91.5%), sodium bicarbonate (78%), solutions for volume replacement (62.8%), methylxanthines (56.7%) and catecholamines (52.4%). It may be concluded that the pattern of drug usage indicates a high incidence of proven or suspected infections and circulatory and respiratory disorders reflecting the high-risk state of study infants.