Wolfgang Strohmaier

D-erythro-neopterin plasma levels in intensive care patients with and without septic complications

The activation of macrophages is accompanied by release of 2-amino-4-oxo-6(D-erythro-l′,2′,3′-trihy-droxypropyl)-dihydropteridine (D-erythro-neopterin). The neopterin levels of 21 patients were measured with radioimmunoassay. The patients were classified according to the clinical course and outcome. We found highly significant differences between survivors and nonsurvivors for each of the evaluated days of the observation period. In addition to a sustained increase, patients with fatal outcome always showed a higher percentage of neopterin levels (88.2 ± 28 [sd]%) exceeding the upper confidence limit (27.4 nmol/L) than survivors (31.8 ± 29.9%). We conclude that the assessment of D-erythro-neopterin might be an easily available aid for an early evaluation of the immunologic status of a patient at risk for septic complications.

Surfactant therapy in infants and children: three years experience in a pediatric intensive care unit.

Despite the established success of surfactant application in neonates, the use of surfactant in older children is still a matter of discussion. We hypothesized that surfactant application in children with acute respiratory distress syndrome (ARDS) secondary to a pulmonary or systemic disease or after cardiac surgery improves pulmonary function. We also asked whether repeated treatment could further improve pulmonary function. To answer these questions, we measured oxygenation index (OI) and hypoxemia score after the first and after a second application of surfactant (50–100 mg/kg body wt) at least 24 h later. We enrolled 19 children (older than 4 weeks) for a retrospective chart review study, and six of them underwent cardiac surgery. Demographic data were extracted. OI and hypoxemia score were estimated before and 2 and 24 h after surfactant application. Lung injury score was calculated before and 24 h after surfactant application. Outcome measures included survival, duration of mechanical ventilation, and pediatric ICU and hospital stay. The median patient age was 9.0 (quarter percentile 3.7/25) months. The median weight was 8.4 (4.1/11.5) kg. The median lung injury score before the first surfactant application was 2.3 (2.3/2.6). Hospital duration and pediatric ICU stay for all patients was 31.0 (20.0/49.5) days and 27.0 (15.5/32.5) days, respectively. The duration of mechanical ventilation was 24.0 (18.5/31.0) days. The overall mortality was 53%. Twenty-four hours after the first surfactant application, pulmonary function significantly improved. The median OI was 14 (5.5/26) before and 7 (4.5/14.5) 24 h after surfactant application (P = 0.027). The hypoxemia score was 91.7 (69.9/154.2) before and 148.4 (99.2/167.6) 24 h after surfactant application (P = 0.0026). Seven children received a second application, which did not further improve pulmonary function. The lung injury score was not influenced by either surfactant application. We conclude that a single surfactant application improves pulmonary function in children with ARDS. A second application of surfactant showed no further benefit. Outcome was not affected in our study population.

Protection against endotoxemia in rats by a novel tetrahydrobiopterin analogue.

We studied the effects of a novel pterin antagonist of NO synthase, the 4-amino analogue of tetrahydrobiopterin (4-ABH4), in a rat model of endotoxic shock and compared its properties with those of N(G)-monomethyl L-arginine (L-NMMA). Treatment with a bolus dose of 4-ABH4 at 2 h after LPS challenge significantly improved the 6-day survival rate, compared with the controls treated with saline. L-NMMA treatment did not significantly influence the survival rate. This bolus treatment, using either compound, had no effect on the plasma nitrite + nitrate or plasma IL-6 levels. The continuous infusion of 4-ABH4 efficiently suppressed the enhanced calcium-dependent/independent NO synthase activities induced by endotoxin in lung homogenates and completely suppressed the increase in plasma nitrite + nitrate caused by endotoxin at 5 h, with no significant difference compared with the L- NMMA treatment. Treatment of RAW264.7 murine macrophages with 4-ABH4 but not with L-NMMA suppressed endotoxin-induced tumor necrosis factor-alpha release by the cells, whereas nitrite in the supernatant decreased in a dose-dependent fashion in both assay systems. Our data show that 4-ABH4, an inhibitor of inducible NO synthase, significantly improves survival in a rat model of endotoxic shock when administered in a bolus dose that does not reduce plasma total nitrite + nitrate levels. Because we observed no overt signs of toxicity and no influence on organ-specific tetrahydrobiopterin levels, we conclude that the novel compound 4-ABH4 is a promising drug candidate for protection against endotoxin-related mortality.

A 4-amino analogue of tetrahydrobiopterin attenuates endotoxin-induced hemodynamic alterations and organ injury in rats.

Most recently we have shown that 4-aminotetrahydrobiopterin (4-ABH4), an analogue of tetrahydrobiopterin (cofactor of NO synthase), even administered 2 h after endotoxin challenge, improves survival rate in rats. The following experiment was performed to examine the effects of 4-ABH4 with respect to endotoxin-induced hemodynamic alterations and organ failure. At 2 h after endotoxic challenge (10 mg kg−1 body weight) animals received 4-ABH4 at a dose of 1, 10, or 100 mg kg−1 body weight. The controls were treated similarly but received saline at the same volume. Eight hours after endotoxin challenge cardiac index and stroke volume were significantly increased in animals treated with 10 mg 4-ABH4 compared to controls (0.23 ± 0.06 vs. 0.16 ± 0.04 mL min−1 kg−1 and 0.29 ± 0.05 vs. 0.22 ± 0.03 mL beat−1) while mean arterial pressure and peripheral vascular resistance index did not significantly differ among the groups. Plasma alanine aminotransferase (ALT) and creatinine levels were significantly increased in endotoxin controls compared with laboratory controls (ALT: 1643 ± 1436 vs. 74 ± 17 U L−1; Creatinine: 91 ± 29 vs. 42± 3 &mgr;mol L−1) which was attenuated in animals treated with 10 mg kg−1 4-ABH4 (ALT: 417 ± 318 U L−1; Creatinine: 78 ± 26 &mgr;mol L−1). Moreover, endotoxin-induced lung edema and intestinal necrosis were significantly reduced by 4-ABH4. Our study provides information that tetrahydrobiopterin analogue, 4-ABH4, improves LPS induced hemodynamic conditions and organ injury. This may, at least in part, account for the previously observed protection of rats by 4-ABH4 against endotoxin-induced mortality in the same endotoxic shock model.

Pteridine and nitrite/nitrate formation in experimental septic and traumatic shock.

ABSTRACT Bacterial lipopolysaccharides (LPS) induce the activity of guanosine triphosphate (GTP)-cyclohydrolase I (GTP-CHI), the first enzyme in the biosynthesis of tetrahydrobiopterin (H4bip) from GTP in endothelial cells and macrophages. In these and other cells, LPS also acts costimulatory with cytokines, i.e., mainly tumor necrosis factor-± (TNF-±). H4bip is the cofactor for nitric oxide synthase (NOS). We were interested in comparing the pteridine and nitrate levels in two baboon models: a hyperdynamic sepsis model and a hemorrhagic traumatic shock model. Our results show a similar response of pteridines (H4bip, neopterin) and nitrite/nitrate levels to an immune stimulus. LPS, which peaks rapidly, induces a sustained increase in pteridine levels in septic animals. Since hemorrhagic animals show very little response in terms of cytokine production, it was not possible to measure the induction of neopterin and nitrite/nitrate. This information could aid our understanding of the regulatory mechanisms in various forms of experimental shock.

Surfactant application during extracorporeal membrane oxygenation improves lung volume and pulmonary mechanics in children with respiratory failure

IntroductionThis study was performed to determine whether surfactant application during extracorporeal membrane oxygenation (ECMO) improves lung volume, pulmonary mechanics, and chest radiographic findings in children with respiratory failure or after cardiac surgery.MethodsThis was a retrospective chart review study in a pediatric intensive care unit (PICU). Seven patients received surfactant before weaning from ECMO was started (group S). They were compared to six patients treated with ECMO who did not receive surfactant (group C). These control patients were matched based on age, weight, and underlying diagnosis. Demographic data, ventilator settings, tidal volume, compliance of respiratory system (calculated from tidal volume/(peak inspiratory pressure – positive end-expiratory pressure), and ECMO flow were extracted. Chest radiographs were scored by two blinded and independent radiologists. Changes over time were compared between groups by repeated-measures analysis of variance (time*group interaction). Values are given as percentages of baseline values.ResultsThe groups did not differ with regard to demographic data, duration of ECMO, ventilator settings, PICU and hospital days. After application of surfactant, mean tidal volume almost doubled in group S (from 100% before to 186.2%; p = 0.0053). No change was found in group C (100% versus 98.7%). Mean compliance increased significantly (p = 0.0067) in group S (from 100% to 176.1%) compared to group C (100% versus 97.6%). Radiographic scores tended to decrease in group S within 48 h following surfactant application. ECMO flow tended to decrease in group S within 10 h following surfactant application but not in group C. Mortality was not affected by treatment.ConclusionSurfactant application may be of benefit in children with respiratory failure treated with ECMO, but these findings need confirmation from prospective studies.

Early mechanical ventilation is deleterious after aspiration-induced lung injury in rabbits

We investigated whether mechanical ventilation after aspiration is deleterious when started before surfactant therapy. Gas exchange and lung mechanics were measured in rabbits after aspiration either mechanically ventilated before or after lavage with diluted surfactant or Ringer’s solution. Lung injury was induced by intratracheal instillation of 2 mL/kg of a betain/HCl pepsin mixture. After 30 min of spontaneous breathing, ventilation was started in 12 rabbits, which were then treated by lavage with diluted surfactant (15 mL/kg body weight; 5.3 mg/mL, group MVpre S) or with Ringer’s solution (1 mL/kg; group MVpre R). Another 12 rabbits were treated by lavage while spontaneously breathing and were then connected to the ventilator (MVpost S and MVpost R). Sham control rabbits were mechanically ventilated for 4 h. At the end of experiment, PaO2/FiO2 ratio in MVpost S was five times higher than in MVpre S (P = 0.0043). Lung mechanics measurements showed significant difference between MVpre S and MVpost S (P = 0.0072). There was histopathologic evidence of decreased lung injury in MVpost S. Immediate initiation of ventilation is harmful when lung injury is induced by aspiration. Further investigations are needed to clarify whether the timing of lavage with diluted surfactant has an impact on the treatment of patients with aspiration or comparable types of direct lung injury.

Neopterin Blood Levels: A Basis for Deciding to Use Antibiotics in Intensive Care Unit (ICU) Patients

Summary The hypothesis that neopterin blood levels provide a reliable basis for the decision to use antibiotics was tested prospectively in 536 traumatised intensive care unit (ICU) patients. Where infection was suspected antibiotics were given either if deemed necessary (control group) or if neopterin levels were>40 nmol/L (study group). The number of patients with infections (24% vs. 29%), the number of infectious episodes per patient (3.1 vs. 4.8 ), the incidence of infections with Staphylococcus and Pseudomonas, and the treatment costs (minus 20%) were lower in the study group. Mean length of ICU stay and outcome remained unchanged. We conclude that it is beneficial to base the decision to use antibiotics in ICU patients with suspected infections on neopterin testing.

Mechanical Properties of the Lungs of Posttraumatic Rats Are Improved by Including Fat in Total Parenteral Nutrition

Posttraumatic lung failure is often associated with alterations in lung surfactant composition and function. Our previous studies with total parenteral nutrition (TPN) have shown the effect of fat supply on phospholipid composition in pulmonary surfactant. Consequently, we attempted to determine whether fat supply would also improve the functional properties of the lung and surfactant. After polytrauma consisting of laparotomy, hypovolemia, and a single femur fracture, the animals were fed only parenterally for 14 days. Two groups of rats were infused via the jugular vein with isocaloric (260 kcal/kg/day) and isonitrogenous (5.62 gN/kg/day) regimens. The nonprotein calories were given either as glucose alone or 30% of calories as fat. Lung function was assessed by measurement of static lung compliance and total lung capacity. Surfactant isolated from lavage fluid was evaluated by means of a Wilhelmy balance. In agreement with our previous studies, in which we obtained a higher level of saturated lecithin in the fat groups, we found significantly (p less than 0.05) increased compliance (2.93 +/- 0.54 ml/cm H2O/kg BW) in the fat group compared to the carbohydrate group (2.02 +/- 0.36 ml/cm H2O/kg BW). Furthermore, a significantly (p less than 0.05) elevated total lung capacity was noted in the fat group (32.60 +/- 3.90 vs 26.00 +/- 1.45 ml/kg BW). The relatively improved surface tension properties as expressed by stability index (S = 0.89 +/- 0.24 vs 0.66 +/- 0.22) and minimum surface tension (gamma min = 18.5 +/- 5.01 vs 20.75 +/- 2.81) is a characteristic change, and was seen in the fat group.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of Parenteral Nutrition on Phospholipid Metabolism in Posttraumatic Rat Lungs

In the current investigation, we studied two groups of rats--one group supplied exogenous phospholipid precursors (carbohydrate plus fat emulsion group) and the other given only calories (carbohydrate group)--to evaluate the effects on surfactant composition by normocaloric alimentation, using a hypovolemic-traumatic shock model. The total phospholipid (PHL) contents of lung tissue were similar in both groups. However, we found differences in the dipalmitoylphosphatidylcholine fraction (DPPC--the most important component of surfactant material) in both lung tissue and lavage fluid. With lipid emulsion, there was an increased fraction of saturated lecithins (mainly DPPC) both in lung tissue and lavage fluid, similar to former studies with hypocaloric alimentation. In this model, those findings suggest that the PHL pattern does not depend on the quantity of caloric supply, but, rather, on the infusion composition. The enhanced DPPC content is further reflected in improved surfactant status: lipid in parenteral nutrition (PN) may exert a direct salutary effect on lung mechanics.