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Biomedical subjects

Peter Radermacher

Publications and source records attributed to Peter Radermacher.

At least 19 recordsLinked to original sources
PubMed2007

Effects of combining inducible nitric oxide synthase inhibitor and radical scavenger during porcine bacteremia.

Complex interactions of nitric oxide and other free radicals have been implicated in the pathogenesis of sepsis and organ dysfunction. We hypothesized that simultaneous inducible nitric oxide synthase inhibition (L-N6-[1-iminoethyl]-lysine [L-NIL]) and neutralization of superoxide (O2-) (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl [Tempol]) would protect from detrimental consequences of long-term, volume-resuscitated, hyperdynamic porcine bacteremia. In this prospective, randomized, controlled experimental study, 16 anesthetized, mechanically ventilated and instrumented pigs were exposed to 24 h of continuous infusion of live Pseudomonas aeruginosa. After 12 h of hyperdynamic sepsis, animals were randomized to receive either vehicle (control, n = 8) or combination of L-NIL and Tempol (n = 8). Systemic and hepatosplanchnic hemodynamics, oxygen exchange, metabolism, ileal mucosal microcirculation and tonometry, oxidative stress and coagulation parameters were assessed before, 12, 18, and 24 h of P. aeruginosa infusion. Combined treatment inhibited sepsis-induced increase in plasma nitrate/nitrite, 8-isoprostane, and thiobarbituric acid reactive species concentrations, prevented hypotension, and reversed hyperdynamic circulation. Despite lower intestinal macrocirculation, combined regimen attenuated the otherwise progressive deterioration in ileal mucosal microcirculation and prevented mucosal acidosis. Treatment substantially attenuated mesenteric and hepatic venous acidosis, preserved sepsis-induced impairment of hepatosplanchnic redox state, and prevented the development of renal dysfunction. Finally, coinfusion of L-NIL and Tempol largely attenuated the sepsis-induced rise in plasma von Willebrand factor and thrombin-antithrombin complexes. Thus, hemodynamic, microcirculatory, metabolic, renal, and coagulation data indicate that combining inducible inhibition with cell permeable O2(-) radical scavenger afforded significant protection in porcine sepsis, thus suggesting an important interactive role of O2(-) and nitric oxide in mediating organ dysfunction.

Animals↗
PubMed2006

Effects of 15-deoxy-Delta12,14-prostaglandin-J2 during hyperdynamic porcine endotoxemia.

OBJECTIVE: To investigate the hemodynamic and metabolic effects of the peroxisome proliferator-activated receptor (PPAR)-gamma ligand and nuclear-factor (NF)-kappa B inhibitor 15-deoxy-Delta12,14-prostaglandin-J2 (15d-PGJ2) during long-term, hyperdynamic porcine endotoxemia. DESIGN: Prospective, randomized, controlled experimental study with repeated measures. SETTING: Investigational animal laboratory. SUBJECTS: 19 anesthetized, mechanically ventilated and instrumented pigs. INTERVENTIONS: At 12 h of continuous intravenous endotoxin and hydroxyethylstarch to keep mean arterial pressure (MAP)>60 mmHg, swine randomly received vehicle (control group, n=10) or 15-deoxy-Delta12,14-prostaglandin-J2 (15d-PGJ2 group, n=9; 1 microg kg(-1) min(-1) loading dose during 1 h; thereafter,0.25 microg kg(-1) min(-1) for 11 h). MEASUREMENTS AND RESULTS: Hemodynamic, metabolic and organ function parameters were assessed together with parameters of nitric oxide production and oxidative stress. 15d-PGJ2 prevented the endotoxin-induced progressive hypotension, due to a positive inotropic effect, which resulted in a significantly higher blood pressure during the treatment phase and prevented the rise in hepatic vein alanine-aminotransferase activity. It did not affect, however, any other parameter of organ function nor of nitric oxide production, proinflammatory cytokine release or lipid peroxidation (8-isoprostane). CONCLUSIONS: 15d-PGJ2 stabilized systemic hemodynamics, due to improved myocardial performance, and resulted in an only transient effect on alanine-aminotransferase activity, without further beneficial effect on endotoxin-induced metabolic and organ function derangements. Low tissue 15d-PGJ2 concentrations and/or the delayed drug administration may explain these findings.

Animals↗
PubMed2006

Catecholamines and vasopressin during critical illness.

In critical care medicine, catecholamines are most widely used to reverse circulatory dysfunction and thus to restore tissue perfusion. However, catecholamines not only influence systemic and regional hemodynamics, but also exert a variety of significant metabolic, endocrine, and immunologic effects. Arginine vasopressin is a vasomodulatory hormone with potency to restore vascular tone in vasodilatory hypotension. Although the evidence supporting the use of low doses of vasopressin or its analogs in vasodilatory shock is increasing, lack of data regarding mortality and morbidity prevent their implementation in critical care protocols.

Catecholamines↗
PubMed2006

Catecholamines and vasopressin during critical illness.

This article summarizes the effects of catecholamines and vasopressin on the cardiovascular system, focusing on their metabolic and immunologic properties. Particular attention is dedicated to the septic shock condition.

Catecholamines↗
PubMed2006

Role of inducible nitric oxide synthase in the reduced responsiveness of the myocardium to catecholamines in a hyperdynamic, murine model of septic shock.

OBJECTIVES: Excess nitric oxide production is a key mediator of hypotension and catecholamine-resistance in septic shock. Although nitric oxide synthase blockade has been shown to restore hemodynamics, conflicting results on myocardial function were reported. Inducible nitric oxide synthase (iNOS) knockout (iNOS-/-) mice showed improved heart function, but these results were obtained during hypodynamic shock characterized by reduced cardiac output. Therefore, we investigated heart function and catecholamine responsiveness in a clinically relevant, murine model of cecal ligation and puncture (CLP)-induced septic shock. DESIGN: Prospective, controlled, randomized animal study. SETTING: University animal research laboratory. SUBJECTS: Male C57Bl/6 wild-type and iNOS-/- mice. INTERVENTIONS: Fifteen hours after CLP, three groups of mice (wild-type controls, n = 9; iNOS-/-, n = 12; and wild-type mice receiving 5 mg x kg(-1) intraperitoneally of the selective iNOS inhibitor GW274150 immediately after CLP, n = 8) were anesthetized, mechanically ventilated, and instrumented (central venous and left ventricular pressure-conductance catheter). Measurements were recorded 18, 21, and 24 hrs post-CLP. Hydroxyethylstarch and norepinephrine were infused to achieve normotensive and hyperdynamic hemodynamics. MEASUREMENTS AND MAIN RESULTS: There was no intergroup difference in mean arterial pressure, stroke volume, and left ventricular ejection fraction. Norepinephrine doses required to achieve the hemodynamic targets were lower in GW274150 (p < .001 vs. controls) and even further reduced in iNOS-/- mice (p < .001 vs. controls, p < .001 vs. GW274150). In the control group, the higher norepinephrine doses resulted in significantly higher heart rates and consequently cardiac output, maximal contraction, and relaxation than in the GW274150 and iNOS-/- animals. Left ventricular end-diastolic volume was also significantly higher in the controls than in the GW274150 and iNOS-/- mice, whereas left ventricular end-diastolic pressure did not differ. CONCLUSIONS: Our results confirm septic shock-related impaired left ventricular function. Genetic iNOS deletion and pharmacologic iNOS blockade enhanced cardiac norepinephrine responsiveness due to improved systolic function. In contrast, iNOS inhibition seemed to be affiliated with compromised left ventricular relaxation.

Animals↗
PubMed2006

The parp-1 inhibitor ino-1001 facilitates hemodynamic stabilization without affecting DNA repair in porcine thoracic aortic cross-clamping-induced ischemia/reperfusion.

Inhibition of poly (ADP-ribose) polymerase 1 (PARP-1) improved hemodynamics and organ function in various shock models induced by sepsis or ischemia/reperfusion. PARP-1, however, is also referred to play a pivotal role for the maintenance of genomic integrity. Therefore, we investigated the effect of the PARP-1 blocker INO-1001 on hemodynamics, kidney function, and DNA damage and repair during porcine thoracic aortic cross-clamping. The animals underwent 45 min of aortic cross-clamping after receiving vehicle (n=9) or i.v. INO-1001 (n=9; total dose, 4 mg.kg, administered both before clamping and during reperfusion), data were recorded before clamping, before declamping, and 2 and 4 h after declamping. During reperfusion, continuous i.v. norepinephrine was incrementally adjusted to maintain blood pressure greater than or equal to 80% of the pre-clamping level. The plasma INO-1001 levels analyzed with high-pressure liquid chromatography were 1 to 1.4 micromol/L and 0.4 to 0.6 micromol/L before and after clamping, respectively. Although INO-1001-treated animals required less norepinephrine support, kidney function was comparable in the 2 groups. There was no intergroup difference either in the time course of DNA damage and repair (comet assay) as assessed both in vivo in whole blood before surgery, before clamping, before declamping, 2 h after declamping, and ex vivo in isolated lymphocytes (Ficoll gradient) sampled immediately before clamping and analyzed before, immediately, and 1 and 2 h after exposure to 4 bar 100% O2 for 2 h. There was no difference either in the expression of the cyclin-dependent kinase inhibitor gene, p27, in the kidney (immunohistochemistry). The reduced norepinephrine requirements during reperfusion suggest a positive inotropic effect of INO-1001, as demonstrated by other authors. In our model, INO-1001 proved to be safe with respect to DNA repair.

Animals↗
PubMed2005

Plasma disappearance of indocyanine green: a marker for excretory liver function?

OBJECTIVE: To investigate whether the plasma disappearance rate of indocyanine green (ICG) assessed using a commercially available bedside monitor provides an accurate estimation of cumulative biliary ICG excretion in a clinically relevant model of long-term, hyperdynamic porcine endotoxemia. DESIGN AND SETTING: Prospective experimental study in the animal laboratory in a university hospital. SUBJECTS: Fifteen domestic pigs. INTERVENTIONS: Pigs were anesthetized, mechanically ventilated, and instrumented. Intravenous endotoxin was continuously infused over 12 h concomitant with fluid resuscitation. Measurements were performed before and 12 h after the start of endotoxin infusion. MEASUREMENTS AND RESULTS: All animals developed hyperdynamic circulation characterized by a sustained increase in cardiac output. Despite well maintained portal venous and consequently total liver blood flow endotoxemia decreased hepatic lactate uptake, which was accompanied by a significant fall in portal and hepatic venous pH. Both the cumulative bile flow and biliary ICG and bicarbonate excretion measured during 1 h after intravenous bolus of 25 mg ICG fell significantly. By contrast, neither the plasma disappearance rate of ICG nor the rate corrected for liver blood flow exhibited any changes over time. CONCLUSIONS: In hyperdynamic porcine endotoxemia the plasma disappearance rate of ICG failed to accurately substitute for direct short-term measures of biliary ICG excretion. Hence normal values of plasma disappearance rate of ICG should be interpreted with caution in early, acute inflammatory conditions.

Animals↗
PubMed2005

Validation of portal vein flow measurement by color flow Doppler sonography in a porcine model of septic shock.

OBJECTIVE: To compare portal vein flow values gained by color flow Doppler sonography with simultaneously derived data from an ultrasound transit time flow probe. DESIGN: Repeated, simultaneous flow measurements were performed in a prospective study investigating the effect of various drugs on hepatosplanchnic perfusion and energy balance in a long-term model of stable, hyperdynamic endotoxin shock. SETTING: Investigational animal laboratory. SUBJECTS: Domestic pigs. INTERVENTIONS: Alterations in respirator setting were studied with regard to their effect on the quality of color flow Doppler data in comparison to flow probe data. Additional experiments included variation in PEEP level in conjunction with volume resuscitation. MEASUREMENTS AND RESULTS: Respiratory rates of 14-18/min led to color Doppler flow values consistently 20-40% above simultaneously measured flow probe data. Temporary apnea led to enhanced agreement of data. Reduction in respiratory rate to 8/min with increase in tidal volume consistently led to color Doppler data within 10% of the corresponding flow probe values. CONCLUSIONS: A short-term period of respirator-dependent, constant portal vein inflow enables color Doppler sonography to detect correct values in a clinically relevant setting of hyperdynamic endotoxin shock.

Animals↗