Biomedical subjects

Dieter Walmrath

Publications and source records attributed to Dieter Walmrath.

5 recordsLinked to original sources

PubMed2003

Chronic sildenafil treatment inhibits monocrotaline-induced pulmonary hypertension in rats.

Sildenafil, a phosphodiesterase 5 inhibitor, is currently under investigation for therapy of pulmonary hypertension. This study was designed to investigate chronic effects of sildenafil in monocrotaline (MCT)-induced pulmonary hypertension in rats. Four weeks after a single subcutaneous injection of MCT, the animals displayed nearly threefold elevated pulmonary artery pressure and vascular resistance values, with a concomitant decline in central venous oxygen saturation and arterial oxygenation. Marked right heart hypertrophy was evident, and massive thickening of the precapillary artery smooth muscle layer was histologically apparent. Further deterioration of pulmonary hypertension occurred 6 weeks after MCT injection, with some animals dying during this period because of right heart failure. When chronically administered from Days 14-28, sildenafil significantly increased plasma cyclic guanosine monophosphate and inhibited the development of pulmonary hypertension and right heart hypertrophy, with preservation of gas exchange and systemic arterial pressure. A corresponding efficacy profile was also noted for long-term feeding with sildenafil from Days 28-42. Moreover, the death rate significantly decreased in those animals treated with sildenafil. We conclude that sildenafil attenuates MCT-induced pulmonary hypertension and cor pulmonale in rats.

Administration, Oral↗

PubMed2003

Parenteral nutrition with fish oil modulates cytokine response in patients with sepsis.

Infusion of fish oil-based (n-3) lipids may influence leukocyte function and plasma lipids in critical care patients. Twenty-one patients with sepsis requiring parenteral nutrition were randomized to receive an n-3 lipid emulsion rich in eicosapentaenoic acid and docosahexaenoic acid or a conventional (n-6) lipid emulsion (index fatty acid: arachidonic acid) for 5 days. The impact on plasma-free fatty acids, mononuclear leukocyte cytokine generation, and membrane fatty acid composition was examined. Cytokine synthesis by isolated mononuclear leukocyte was elicited by endotoxin. Before the onset of lipid infusion therapy, plasma-free fatty acid concentrations were greatly increased in septic patients, with arachidonic acid by far surpassing eicosapentaenoic acid and docosahexaenoic acid, a feature maintained during conventional lipid infusion. Within 2 days of fish oil infusion, free n-3 fatty acids increased, and the n-3/n-6 ratio was reversed, with rapid incorporation of n-3 fatty acids into mononuclear leukocyte membranes. Generation of proinflammatory cytokines by mononuclear leukocytes was markedly amplified during n-6 and was suppressed during n-3 lipid application. After termination of lipid administration, free n-3 fatty acid concentrations and mononuclear leukocyte cytokine synthesis returned to preinfusion values. Use of lipid infusions might allow us to combine intravenous alimentation with differential impact on inflammatory events and immunologic functions in patients with sepsis.

Critical Illness↗

PubMed2002

Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial.

BACKGROUND: Lung fibrosis can be complicated by pulmonary hypertension, limiting exercise tolerance and life expectancy. Furthermore, vasodilators might cause deterioration in gas exchange. Our aim was to compare acute effects of sildenafil, nitric oxide, and epoprostenol in individuals with pulmonary hypertension secondary to lung fibrosis. METHODS: We did a randomised controlled, open-label trial, in 16 individuals admitted to our hospital with pulmonary hypertension secondary to lung fibrosis. After inhalation of nitric oxide (10-20 ppm), we assigned patients to either maximum tolerated dose of intravenous epoprostenol (mean 8.0 ng/kg per min; n=8) or oral sildenafil (50 mg; n=8). Our primary objective was to assess pulmonary vasodilative potency (decrease in pulmonary vascular resistance index) of sildenafil by comparison with inhaled nitric oxide and infused epoprostenol. Analyses were by intention to treat. FINDINGS: Pulmonary vascular resistance index was reduced by nitric oxide (-21.9%, 95% CI -14.1 to -36.2), epoprostenol (-36.9%, -24.4 to -59.6), and sildenafil (-32.5%, -10.2 to -54.1). However, ratio of pulmonary to systemic vascular resistance decreased only in individuals who received nitric oxide and sildenafil. Baseline measurement of multiple-inert-gas elimination showed right-to-left shunt flow (4.8%, 0.0-28.2) and little perfusion of low ventilation(V)/perfusion(Q) areas (0.1%, 0.0-13.0). Prostacyclin increased V/Q mismatch (shunt 16.8%, 10.8-35.9; low V/Q 3.8%, 0.0-13.0) and decreased arterial oxygenation. By contrast, nitric oxide (4.5%, 0.0-18.0; 0.0%, 0.0-17.3) and sildenafil (3.3%, 0.0-11.3; 0.0%, 0.0-12.4) maintained V/Q matching, with raised arterial partial pressure of oxygen (14.3 mm Hg, -1.7 to 31.3) noted for sildenafil. We recorded no adverse events. INTERPRETATION: Sildenafil causes preferential pulmonary vasodilation and improves gas exchange in patients with severe lung fibrosis and secondary pulmonary hypertension.

Adult↗

PubMed2002

Small-dose nitric oxide improves oxygenation during one-lung ventilation: an experimental study.

UNLABELLED: Inhaled nitric oxide (NO) at 20 or 40 ppm does not improve arterial oxygenation during one-lung ventilation (OLV). The authors hypothesized that NO at smaller concentrations might improve oxygenation. Twelve piglets weighing 26 to 32 kg were studied. When PaO(2) had reached a plateau during OLV, NO at doses of 4, 8, 16, and 32 ppm were randomly administered for 30 min. Hemodynamic data were determined by invasive monitoring. Blood gas analysis and, in six animals, ventilation-perfusion analysis by the multiple inert gas elimination technique were used to characterize pulmonary gas exchange. NO at 4, 8, 16, and 32 ppm improved PaO(2) during OLV. NO at 4 ppm had a more intense effect on arterial oxygenation than doses of 8, 16, and 32 ppm (DeltaPaO(2), 42 +/- 35 mm Hg versus 22 +/- 20 mm Hg, 13 +/- 18 mm Hg, and 15 +/- 16 mm Hg; P < 0.05). NO at 4 ppm reduced intrapulmonary shunt flow, whereas a larger concentration exhibited no statistically significant effect. The authors conclude that NO improves arterial oxygenation more effectively at smaller doses than at larger doses. This dose-dependent effect remains to be confirmed in acute hypoxemia during OLV. IMPLICATIONS: Inhaled nitric oxide at 4 ppm improves arterial oxygenation during one-lung ventilation to a greater extent than larger doses, and this effect is caused by a reduction in intrapulmonary shunt.

Animals↗

PubMed2002

Pharmacokinetics and metabolism of infused versus inhaled iloprost in isolated rabbit lungs.

Iloprost is a potent prostacyclin analog, which has been shown to exert beneficial effects in several vascular disorders. Inhalation of aerosolized iloprost was found to cause selective pulmonary vasodilatation, and this approach is under current investigation for treatment of chronic pulmonary hypertension. The present study investigated pharmacokinetics and metabolism of aerosolized iloprost in isolated buffer-perfused rabbit lungs, compared with intravascular administration of the prostanoid. After buffer admixture of iloprost, a steady decline of perfusate concentrations of the intact prostanoid was noted (half-life approximately 3.5 h), mostly attributable to progressive metabolism to dinor- and tetranoriloprost. Inhaled iloprost rapidly entered the intravascular compartment, with peak buffer concentrations being noted after 30 min (bioavailability approximately 63%). Compared with infused iloprost, significantly more rapid metabolism to dinor- and tetranoriloprost was noted for iloprost administered via the inhalative route of application. However, the percentage of the nebulized agent that enters the intravascular space as intact iloprost displays the same clearance rate as directly perfusate-admixed prostanoid. We conclude that a high percentage of inhaled iloprost rapidly enters the intravascular compartment in intact rabbit lungs. The lung is capable of metabolizing iloprost via beta-oxidation, and more rapid appearance of dinor- and tetranoriloprost is noted for the inhalative as compared with the intravascular route of iloprost administration.

Administration, Inhalation↗