Pulmonary complications after bone marrow transplantation in children: twenty-four years of experience in a single pediatric center.

In children, pulmonary sequelae contribute to early and late morbidity after bone marrow transplantation (BMT). Between 1975-1999, we performed 152 BMTs in 138 pediatric patients with malignant and nonmalignant diseases. Allogenic bone marrow was used from 99 HLA identical siblings and from 23 other related or unrelated donors. Autologous marrow was used in 30 transplantations. Median age was 8. 6 years (range, 1.1-22.4) at time of BMT. The median survival was 42%, the survival time was 6.5 years (range, 0.8-23.1), and the median follow-up time was 6.8 years (range, 0.8-23.2). Seventeen patients had severe respiratory complications. Early severe respiratory complications leading to death within the first 4 months after BMT were due to pulmonary edema (n = 1), or fungal (n = 3), bacterial (n = 1), or viral (n = 2) pneumonia. Late severe respiratory sequelae were defined as persistent respiratory symptoms for more than 4 months despite treatment, and these occurred in 10 patients, of whom 5 died. Underlying diagnoses covered a wide spectrum, including bronchiolitis obliterans (n = 3), severe restrictive lung disease (n = 2), idiopathic pneumonia syndrome (n = 3), chronic bronchitis (n = 1), and hepatopulmonary syndrome (n = 1). The overall probability for death was 0.58, and for death from severe respiratory complications, 0.16. With improved HLA matching, fewer BMTs after relapsed or primary progressive disease, and improved supportive care, including the usage of CMV negative blood products, after 1990 the probability of death from severe respiratory complications was only 0.04, whereas before 1990 it was 0.23 (P = 0.029; in each time period, n = 69). The disease spectrum has changed from initially more infectious complications to bronchiolitis obliterans and idiopathic pneumonia syndrome. Lung function measurements performed in 85 of 138 patients usually showed a mild restrictive pattern. To identify those children as early as possible who are at risk for severe respiratory complications, a close longitudinal follow-up after BMT by pediatric pulmonologists is necessary.

Relapse and clonal disease in children with aplastic anemia (AA) after immunosuppressive therapy (IST): the SAA 94 experience. German/Austrian Pediatric Aplastic Anemia Working Group.

Since the introduction of combined immunosuppressive therapy (IST) into management of aplastic anemia (AA) in childhood response and probability of survival improved. In contrast to bone marrow transplantation (BMT), however, patients after IST are not considered cured as high rates of relapse and development of clonal disease demonstrate. From 11/93 to 9/97 114 children (65 m, 49 f; median age 9.5 y.) from 37 centers in Germany and Austria were registered in the SAA 94 study. 86 patients lacking a matched sibling donor received IST. Most of the patients suffered from very severe (VSAA: PMN < 200/microliter) or severe AA (SAA: PMN < 500/microliter). All patients were treated with combined IST consisting of ALG and Cyclosporin A (CSA). VSAA and SAA patients were additionally treated with G-CSF. Therapy response was evaluated at day 112, after 6, 12 and 18 months. 8/86 patients died, the probability of survival being 87% after 4 years. At d 112 61% of evaluable patients became independent of transfusions (IST response: CR + PR), 13% with normal blood counts (CR). After 6 months 33% showed CR. At 12 and 18 months response improved to 74% resp. 80%, 39% resp. 55% CR. The best response was achieved in the subgroup of VSAA with 90% (PR + CR) and 65% CR after 18 months. 4 patients developed AML 3-19 months after the beginning of IST. In 2/4 pts. an aberrant clone (-7; 5q-) could be detected retrospectively in BM at diagnosis of AA. 3 nonresponders developed chromosomal aberrations (+19; -7, +12; +8) after 4, 12 and 16 months without morphological signs of AML or MDS. Overall 11 relapses occurred at a median time of 12 months (range 5-27 months) after the beginning of IST. 2 of them relapsed under CSA therapy, 2 under tapering of CSA and 7 after cessation of CSA. 7 patients responded again to CSA monotherapy. Overall response rate is 77% with a probability of event free survival (EFS) of 54% after 4 years regarding all complications mentioned as events.

[Beta activation following the intravenous administration of benzodiazepines and the specific antagonist flumazenil (Ro 15-1788)]. / Beta-Aktivierung nach intravenöser Gabe von Benzodiazepinen und dem spezifischen Antagonisten Flumazenil (Ro 15-1788).

In a prospective randomized study involving 32 male subjects aged 18 to 38, the effects of flunitrazepam (0.25 to 2 mg/70 kg), lormetazepam (0.5 to 4 mg/70 kg), midazolam (1.5 to 12 mg/70 kg) and diazepam (4 to 32 mg/70 kg) on the beta-activity (13 to 20/s) were investigated. Each subject received four benzodiazepine injections of increasing dosage. The doses were selected so that the lowest had only a slight effect on the test person's condition, while the highest resulted in deep sedation. The increase in beta-activity started off with a latency of 30 to 60 s; it was proportional to the dosage and reached its maximum between the 2. and 3. minutes. The subsequent decrease in beta-activity could be represented by an exponential function. The effect could be cancelled temporarily by administering repeated doses of the specific antagonist, flumazenil (0.1, 0.3 and 0.9 mg/70 kg). The method is suited for describing pharmacodynamic processes, determining equipotential doses of benzodiazepines and detecting the interaction between benzodiazepines and specific antagonists.

Concomitant increase in plasma atrial natriuretic peptide and cyclic GMP during volume loading.

To investigate the effects of fluid expansion on endogenous atrial natriuretic peptide (ANP) and cyclic 3',5'-guanosine monophosphate (cGMP), four male volunteers were studied before, during and after intravasal volume loading. Volume expansion was performed by intravenous infusion of 2,000 ml isotonic saline solution within 30 min. Mean plasma ANP levels increased 2.5-fold from 31.2 pg/ml to 81.7 pg/ml 40 min after the start of infusion. Plasma cGMP levels paralleled the rise in ANP, showing a mean cGMP increment from 2.7 pmol/ml to a maximum of 8.2 pmol/ml. Both ANP and cGMP levels were back to basal levels 120 min after termination of the infusion. Stimulation of endogenous ANP release by volume loading suggests that ANP is involved in the regulation of fluid homeostasis in man. The parallel rise in plasma cGMP levels supports the idea that cGMP is a mediator for the effects of ANP.