F Simon

Effects of intravenous sulfide during resuscitated porcine hemorrhagic shock

Objective:Controversial data are available on the effects of hydrogen sulfide during hemorrhage. Because the clinical significance of hydrogen sulfide administration in rodents may not be applicable to larger species, we tested the hypothesis whether intravenous Na2S (sulfide) would beneficially influence organ dysfunction during long-term, porcine hemorrhage and resuscitation. Design:Prospective, controlled, randomized study. Setting:University animal research laboratory. Subjects:Forty-five domestic pigs of either gender. Interventions:Anesthetized and instrumented animals underwent 4 hrs of hemorrhage (removal of 40% of the blood volume and subsequent blood removal/retransfusion to maintain mean arterial pressure at 30 mm Hg). Sulfide infusion was started 2 hrs before hemorrhage, simultaneously with blood removal or at the beginning of retransfusion of shed blood, and continued for 12 hrs. Resuscitation comprised hydroxyethyl starch and norepinenephrine infusion titrated to maintain mean arterial pressure at preshock values. Measurements and Main Results:Before, immediately at the end of and 12 and 22 hrs after hemorrhage, we measured systemic and regional hemodynamics (portal vein, hepatic and right kidney artery ultrasound flow probes) and oxygen transport, nitric oxide and cytokine production (nitrate+nitrite, interleukin-6, tumor necrosis factor-&agr; levels). Postmortem biopsies were analyzed for histomorphology (hematoxylin and eosin staining) and DNA damage (terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling staining). The progressive kidney (creatinine levels, creatinine clearance), liver (transaminase activities, bilirubin levels), and cardiocirculatory (norepipnehrine requirements, troponin I levels) dysfunction was attenuated in the simultaneous treatment group only, which coincided with reduced lung, liver, and kidney histological damage. Sulfide reduced mortality, however, irrespective of the timing of its administration. Conclusions:While the sulfide-induced protection against organ injury was only present when initiated simultaneously with blood removal, it was largely unrelated to hypothermia. The absence of sulfide-mediated protection in the pretreatment protocol may be due to the accumulation of sulfide during low flow states. In conclusion, sulfide treatment can be effective in hemorrhagic shock, but its effectiveness is restricted to a narrow timing and dosing window.

ERYTHROPOIETIN DURING AORTIC BALLOON-OCCLUSION-INDUCED ISCHEMIA-REPERFUSION INJURY

TOWARDS RESOLVING THE CHALLENGE OF SEPSIS DIAGNOSTIC. Thomas Herget* and Thomas Joos . *Merck KGaA, Darmstadt, Germany; NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany Biomarkers have proven to be very useful in clinical conditions such as heart attack, stroke and cancer. There are characteristics linked to sepsis like in blood pressure, body temperature and heart rate. Efforts over the last decade to improve diagnosis for infectious inflammation have been unsuccessful in identifying a single and universal biomarker that provides sufficiently high sensitivity and specificity. In gramnegative septicemia and following major abdominal trauma, the determination of endotoxin continues to be a leading candidate which could become adopted into clinical practice. The importance of endotoxin measurement continues to grow as more clinicians recognize the added value of measuring endotoxin in critically ill patients and with the emergence of major pharmaceutical trials directly targeting endotoxin in the bloodstream. However, hundreds of other candidates potentially serving as biomarker for sepsis have been recently described, e.g. cysteinyl-leukotriene (LTC4) generation, procalcitonin (PCT) and C-reactive protein (CRP). However, none of them fulfils the criteria requested by clinicians, namely being specific and sensitive. The presentation will discuss criteria for a sepsis biomarker, will give an overview of obtaining samples from appropriate cell systems and from patients. Furthermore, tools will be described to identify marker candidates on genetic-, proteinand metabolite level. The integration of these data sets covering e.g. signal transduction, protein : protein interaction, gene expression with the help of bioinformatics and systems biology will help to validate such candidates. The final goal is manufacturing a robust diagnostic device for clinical routine work. A solid sepsis diagnostics method will be beneficial for patients, but also for the healthcare systems and will open challenges for the pharmaceutical industry.

Hyperoxia During Porcine Faecal Peritonitis: Ii. The Hepato-Splanchic System:

TOWARDS RESOLVING THE CHALLENGE OF SEPSIS DIAGNOSTIC. Thomas Herget* and Thomas Joos . *Merck KGaA, Darmstadt, Germany; NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany Biomarkers have proven to be very useful in clinical conditions such as heart attack, stroke and cancer. There are characteristics linked to sepsis like in blood pressure, body temperature and heart rate. Efforts over the last decade to improve diagnosis for infectious inflammation have been unsuccessful in identifying a single and universal biomarker that provides sufficiently high sensitivity and specificity. In gramnegative septicemia and following major abdominal trauma, the determination of endotoxin continues to be a leading candidate which could become adopted into clinical practice. The importance of endotoxin measurement continues to grow as more clinicians recognize the added value of measuring endotoxin in critically ill patients and with the emergence of major pharmaceutical trials directly targeting endotoxin in the bloodstream. However, hundreds of other candidates potentially serving as biomarker for sepsis have been recently described, e.g. cysteinyl-leukotriene (LTC4) generation, procalcitonin (PCT) and C-reactive protein (CRP). However, none of them fulfils the criteria requested by clinicians, namely being specific and sensitive. The presentation will discuss criteria for a sepsis biomarker, will give an overview of obtaining samples from appropriate cell systems and from patients. Furthermore, tools will be described to identify marker candidates on genetic-, proteinand metabolite level. The integration of these data sets covering e.g. signal transduction, protein : protein interaction, gene expression with the help of bioinformatics and systems biology will help to validate such candidates. The final goal is manufacturing a robust diagnostic device for clinical routine work. A solid sepsis diagnostics method will be beneficial for patients, but also for the healthcare systems and will open challenges for the pharmaceutical industry.

Hyperoxia During Porcine Faecal Peritonitis: Iii. Effects on Glucose Metabolism:

TOWARDS RESOLVING THE CHALLENGE OF SEPSIS DIAGNOSTIC. Thomas Herget* and Thomas Joos . *Merck KGaA, Darmstadt, Germany; NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany Biomarkers have proven to be very useful in clinical conditions such as heart attack, stroke and cancer. There are characteristics linked to sepsis like in blood pressure, body temperature and heart rate. Efforts over the last decade to improve diagnosis for infectious inflammation have been unsuccessful in identifying a single and universal biomarker that provides sufficiently high sensitivity and specificity. In gramnegative septicemia and following major abdominal trauma, the determination of endotoxin continues to be a leading candidate which could become adopted into clinical practice. The importance of endotoxin measurement continues to grow as more clinicians recognize the added value of measuring endotoxin in critically ill patients and with the emergence of major pharmaceutical trials directly targeting endotoxin in the bloodstream. However, hundreds of other candidates potentially serving as biomarker for sepsis have been recently described, e.g. cysteinyl-leukotriene (LTC4) generation, procalcitonin (PCT) and C-reactive protein (CRP). However, none of them fulfils the criteria requested by clinicians, namely being specific and sensitive. The presentation will discuss criteria for a sepsis biomarker, will give an overview of obtaining samples from appropriate cell systems and from patients. Furthermore, tools will be described to identify marker candidates on genetic-, proteinand metabolite level. The integration of these data sets covering e.g. signal transduction, protein : protein interaction, gene expression with the help of bioinformatics and systems biology will help to validate such candidates. The final goal is manufacturing a robust diagnostic device for clinical routine work. A solid sepsis diagnostics method will be beneficial for patients, but also for the healthcare systems and will open challenges for the pharmaceutical industry.