Summary. In an exploratory study the 24-h urinary excretion pattern of caffeine and 14 of its major metabolites was studied in 32 volunteers (adults, adolescents and children), 14 patients either with end stage renal disease or liver cirrhosis, 7 heavy smokers and 27 patients on therapy with cimetidine, allopurinol, theophylline or phenytoin. Caffeine and its metabolites were quantified by UV:absorption after liquid/liquid-extraction and HPLCseparation, which ensured proper analysis of 1-methyluric acid. In adults the renal excretion of caffeine derivatives corresponded to an intake of 509 mg caffeine/day, with 1-methyluric acid as the predominant metabolite. About 69 % of caffeine was degraded by the paraxanthine pathway, and theobromine- (19 %) and the theophylline pathway (14 % ) were less important. The ratio of paraxanthine formation to urinary caffeine concentration ( = clearance equivalent) was about 2.2 ml. min- 1. kg- ~ in adults, and the corresponding ratios for theophylline and theobromine were 0.43 ml. rain- 1. kg- ~ and 0.59 ml- min: 1 kg-~, respectively. As expected, caffeine degradation was impaired in patients with cirrhosis and was increased in persons who smoked heavily or who were on phenytoin therapy.

In an international multicenter trial infants with clinical and radiological signs of severe RDS (age 2-15 h, birthweight 700-2,000 g, mechanical ventilation, FiO2 greater than or equal to 0.6, no complicating disease) were randomized to receive either a single dose (n = 176) or up to three subsequent doses (n = 167) of a natural porcine surfactant (Curosurf). Using a logistic regression model, the effects of therapy, birthweight, sex, hospital and other clinical factors on survival and various outcome parameters were evaluated. Mortality (13 vs. 21%, p less than 0.05) and the incidence of pneumothorax (9 vs. 18%, p less than 0.01) were significantly lower in the multiple-dose group. Low birthweight, hospital allocation, low Apgar score and initial disease severity were associated with an increased mortality. Low birthweight, hypothermia (admission temperature less than 36 degrees C) and acidosis (pH less than 7.25) prior to surfactant treatment could be identified as risk factors for the development of intracranial hemorrhage.

BACKGROUND AND METHODS:Central catheters are an important prerequisite for adequate parenteral nutrition in preterm infants. However, a variety of complications have been shown to be associated with central lines: septicemica, thrombotic complications, mechanical complications. In this retrospective analysis we summarize our recent experience with central silastic catheters.RESULTS:Within a five-year-period (1986-1990). 497 silastic-catheters were inserted in 366 high risk neonates (mean birthweight 1360 g; 1060-1740 g, 25.-75. percentile) treated at the NICU, Department of Pediatrics, University of Göttingen. 451 catheters which were placed in a central position, were removed after an average duration of 11 days (mean; 8-18 days, 25.-75. percentile). During the observation period, 62.8 percent of the catheters were purposely removed. Making use of the Kaplan-Meier-curve, we calculated how long the catheter could stay without complications; 50% of all catheters could be expected to be in place for 25 days. The incidence of septicemia was 1.9%, bacterial contamination of the catheters was evident in 22% of all central lines. The most predominant microorganisms responsible for catheter-contamination were coagulase-negative staphylococci. In addition, catheters were removed because of signs of phlebitis or suspected thrombotic complications (11.1%), and mechanical complications (dislocation, occlusion; 11.7%). Due to malposition of the central catheter two preterm infants developed pericardial effusions. There was no correlation between the site where the catheter was inserted and these complications.CONCLUSION:Central silastic catheters wherever clinically indicated are a valuable adjunct in the parenteral nutrition on high risk neonates.

There is now convincing evidence that the severity of neonatal respiratory distress syndrome can be reduced by surfactant replacement therapy; however, the optimal therapeutic regimen has not been defined. This randomized European multicenter trial was designed to determine whether the beneficial effects of a single large dose of Curosurf (200 mg/kg) in babies with severe respiratory distress syndrome (arterial to alveolar oxygen tension ratio approximately 0.10) could be enhanced by using multiple doses of surfactant. Preterm neonates (birth weight 700 to 2000 g) with severe respiratory distress syndrome requiring artificial ventilation with fraction of inspired oxygen greater than or equal to 0.6 were randomized into two groups at an age of 2 to 15 hours. Both groups received the usual dose of Curosurf (200 mg/kg) immediately after randomization. In neonates randomized to receive multiple-dose treatment, two additional doses of Curosurf (100 mg/kg each) were instilled into the airways (12 and 24 hours after the initial dose) provided that the patients still needed artificial ventilation with fraction of inspired oxygen greater than 0.21. In both groups (single dose: n = 176, multiple doses: n = 167) there was a rapid improvement in oxygenation as reflected by a threefold increase in arterial to alveolar oxygen tension ratio within 5 minutes after surfactant instillation (P less than .001), and peak inspiratory pressure and mean airway pressure could be reduced significantly during the first 6 hours after surfactant treatment. In addition, ventilatory requirement (peak inspiratory pressure, ventilatory efficiency index) was reduced in the multiple-dose group 2 to 4 days after randomization (P less than .05 to .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Background and methods. Central catheters are an important prerequisite for adequate parenteral nutrition in preterm infants. However, a variety of complications have been shown to be associated with central lines: septicemica, thrombotic complications, mechanical complications. In this retrospective analysis we summarize our recent experience with central silastic catheters. Results. Within a five-year-period (1986-1990), 497 silastic-catheters were inserted in 366 high risk neonates (mean birthweight 1360 g; 1060-1740 g, 25.-75. percentile) treated at the NICU, Department of Pediatrics, University of Gottingen. 451 catheters which were placed in a central position, were removed after an average duration of 11 days (mean; 8-18 days, 25.-75. percentile). During the observation period, 62.8 percent of the catheters werer purposely removed. Making use of the Kaplan-Meiercurve, we calculated how long the catheter could stay without complications; 50% of all catheters could be expected to be in place for 25 days. The incidence of septicemia was 1.9%, bacterial contamination of the catheters was evident in 22% of all central lines. The most predominant microorganisms responsible for catheter-contamination were coagulase-negative staphylococci. In addition, catheters were removed because of signs of phlebitis or suspected thrombotic complications (11.1%), and mechanical complications (dislocation, occlusion; 11.7%). Due to malposition of the central catheter two preterm infants developed pericardial effusions. There was no correlation between the site where the catheter was inserted and these complications. Conclusion. Central silastic catheters whenever clinically indicated are a valuable adjunct in the parenteral nutrition of high risk neonates.

In an exploratory study the 24-h urinary excretion pattern of caffeine and 14 of its major metabolites was studied in 32 volunteers (adults, adolescents and children), 14 patients either with end stage renal disease or liver cirrhosis, 7 heavy smokers and 27 patients on therapy with cimetidine, allopurinol, theophylline or phenytoin. Caffeine and its metabolites were quantified by UV-absorption after liquid/liquid-extraction and HPLC-separation, which ensured proper analysis of 1-methyluric acid.In adults the renal excretion of caffeine derivatives corresponded to an intake of 509 mg caffeine/day, with 1-methyluric acid as the predominant metabolite. About 69 % of caffeine was degraded by the paraxanthine pathway, and theobromine- (19 %) and the theophylline pathway (14 %) were less important. The ratio of paraxanthine formation to urinary caffeine concentration ( = clearance equivalent) was about 2.2 ml.min-1.kg-1 in adults, and the corresponding ratios for theophylline and theobromine were 0.43 ml.min-1.kg-1 and 0.59 ml.min-1.kg-1, respectively. As expected, caffeine degradation was impaired in patients with cirrhosis and was increased in persons who smoked heavily or who were on phenytoin therapy.The results document the possibility of noninvasively investigating gross differences in caffeine disposition by analysis of the urinary pattern of its metabolites.

In an international multicenter trial infants with clinical and radiological signs of severe RDS were randomized to receive either a single dose (n=176) or three subsequent doses (n=167) of a porcine natural surfactant (Curosurf). Using a logistic regression model the effects of therapy, birth weight, sex, and other clinical factors on survival and various outcome parameters were evaluated. Results: Mortality (13vs.21%, p<0.05) and the incidence of pneumothoraces (9vs. 18%, p<0.01) were significantly lower in the multiple-dose group. Low birth weight, hospital allocation, low Apgar and initial disease severity were associated with an increased mortality. Low birth weight, hypothermia (admission temperature <36°C) and acidosis (pH<7.25) prior to surfactant treatment could be identified as risk factors for the development of an intracranial hemorrhage. Conclusion: Mortality and the incidence of pneumothoraces were significantly reduced after multiple-dose treatment of severe RDS as compared to a single dose regimen. 28 day outcome in surfactant treated infants is influenced by various clinical factors.

There is now convincing evidence that the severity of neonatal respiratory distress syndrome can be reduced by surfactant replacement therapy; however, the optimal therapeutic regimen has not been found. The aim of this randomized European Multicenter Trial “Single versus multiple doses” was to reduce the incidence of RDS-associated pulmonary complications as well as mortality in patients receiving multiple doses of surfactant. In this trial, preterm infants (birthweight 700-2000 g) with severe RDS requiring artificial ventilation with FiO2 ≥0.6 were randomized into two groups at an age of 2-15 h. Exclusion criteria have been recently published (Pediatrics 1988, 82, 683-691). Both groups received immediately after randomization the usual dose of Curosurf (200 mg/kg). In infants randomized to receive multiple treatment, two additional doses of Curosurf (100 mg/kg) were instilled into the airway at the age of 12 h and 24 h, provided that the patient still needed artificial ventilation with an FiO2 >0.21. Interim analysis (n=245) showed a reduction of pneumothorax incidence (17% vs. 8,3%); single vs. multiple doses; additionally, the incidence of BPD (17% vs. 10%) and mortality (23% vs. 14%) was reduced in multiple treated patients. Final data of approximately 300 patients included in this trial - which will be finished in april 1990 - will be presented.

In 1979 and 1981 Zelen introduced the so-called prerandomized designs as an alternative to the completely randomized trial of therapies: The participants of the trial are first (pre-) randomized to the treatment groups and asked afterwards for their consent. In the case of binary data, tests for selection and treatment effects in the simple and double prerandomized design are derived and then illustrated by a numerical example.