Project

Back to overview

Time to resuscitation, hemodynamic targets and angiotensin: effects on mitochondrial function and outcome in experimental sepsis

English title Time to resuscitation, hemodynamic targets and angiotensin: effects on mitochondrial function and outcome in experimental sepsis
Applicant Jakob Stephan
Number 127619
Funding scheme Project funding (Div. I-III)
Research institution Forschungsgruppe Intensivmedizin Departement Klinische Forschung Universität Bern
Institution of higher education University of Berne - BE
Main discipline Pathophysiology
Start/End 01.01.2010 - 31.12.2012
Approved amount 468'000.00
Show all

Keywords (8)

Sepsis; Fecal peritonitis; Goal-directed; Mitochondria; septic shock; inflammation; treatment; hormones

Lay Summary (English)

Lead
Lay summary
Infektionen mit Organversagen (schwere Sepsis oder septischer Schock) gehören zu den Krankheiten intensivmedizinischer Patienten mit der höchsten Mortalität. Die genauen Ursachen der Organversagen sind weitgehend unklar, wobei Faktoren wie ungenügende Gewebedurchblutung, systemische Entzündung und direkte metabolische Effekte auf Zellniveau sicher eine Rolle spielen. Zudem werden zunehmend Funktionsstörungen von Mitochondrien angeschuldigt. Interessanterweise wirken nicht nur Hormone auf mitochondriale Funktionen ein sondern auch verschiedene Medikamente, die zur Behandlung von septischen Patienten benutzt werden. Im Rahmen unsers Projekts soll erstens ein klinisch relevantes Model für die Sepsis etabliert werden, und anschliessend anhand dieses Modells Effekte der Sepsis, der intensivmedizinischen Behandlung und endogener vasoregulierender Substanzen auf mitochdondriale Funktionen diverser Organe untersucht werden. Wir erwarten aus unseren Resultaten Einblick in die Regulation mitochondrialer Funktionen in der Sepsis, was zu neuen therapeutischen Konzepten führen könnte. Da bei einer Vielzahl anderer Krankheiten ebenfalls mitochondriale Dysfunktionen beschrieben wurden, könnten unsere Resultate auch weiterreichende Implikationen haben. Infections with organ dysfunctions (severe sepsis or septic shock) are major causes of death in intensive care patients. While the exact reasons for organ dysfunction remain essentially unclear, factors such as inadequate tissue perfusion, systemic inflammation and direct metabolic effects at a cellular level are likely to contribute. Failure of mitochondria to effectively couple oxygen consumption with energy production has been described in sepsis. Interestingly, hormones and drugs frequently used in the treatment of septic patients may also influence mitochondrial functions. Our project aims are first, to establish a clinical relevant model for severe sepsis, and second, to evaluate effects of sepsis per se, the treatment of sepsis, and of endogenous vasoregulating substances on mitochondrial functions of different organs. We expect insights in the regulation of mitochondrial function in sepsis which may have implications for the treatment of this disease. Since mitochondrial dysfunction has been described in various other diseases as well, our results may have an even wider therapeutic impact.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Increasing mean arterial blood pressure in sepsis: effects on fluid balance, vasopressor load and renal function.
Correa Thiago D, Vuda Madhusudanarao, Takala Jukka, Djafarzadeh Siamak, Silva Eliezer, Jakob Stephan M (2013), Increasing mean arterial blood pressure in sepsis: effects on fluid balance, vasopressor load and renal function., in Critical care (London, England), 17(1), 21-21.
Effect of remifentanil on mitochondrial oxygen consumption of cultured human hepatocytes.
Djafarzadeh Siamak, Vuda Madhusudanarao, Takala Jukka, Jakob Stephan M (2012), Effect of remifentanil on mitochondrial oxygen consumption of cultured human hepatocytes., in PloS one, 7(9), 45195-45195.
Effect of treatment delay on disease severity and need for resuscitation in porcine fecal peritonitis.
Corrêa Thiago D, Vuda Madhusudanarao, Blaser Annika Reintam, Takala Jukka, Djafarzadeh Siamak, Dünser Martin W, Silva Eliézer, Lensch Michael, Wilkens Ludwig, Jakob Stephan M (2012), Effect of treatment delay on disease severity and need for resuscitation in porcine fecal peritonitis., in Critical care medicine, 40(10), 2841-9.
Norepinephrine vs. Angiotensin II in septic shock: effects on isolated kidney, heart and liver mitochondrial respiration
Jeger V, Vuda M, Corrêa TD, Takala J, Djafarzadeh S, Jakob SM (2012), Norepinephrine vs. Angiotensin II in septic shock: effects on isolated kidney, heart and liver mitochondrial respiration, in Critical Care, 16(Suppl 1), S71-S71.
Increasing mean arterial blood pressure in sepsis: effects on renal function, fluid balance and vasopressor load
Corrêa TD, Vuda M, Djafarzadeh S, Takala J, Lensch M, Jakob SM (2011), Increasing mean arterial blood pressure in sepsis: effects on renal function, fluid balance and vasopressor load, in Intensive Care Medicine, 37(Suppl 1), S118-S118.
Systemic oxygen consumption and mitochondrial respiration are maintained in lethal porcine fecal peritonitis
Hostettler S, Vuda M, Corrêa TD, Djafarzadeh S, Takala J, Jakob SM (2011), Systemic oxygen consumption and mitochondrial respiration are maintained in lethal porcine fecal peritonitis, in Intensive Care Medicine, 37(Suppl 1), S259-S259.
8. Corrêa TD, Reintam Blaser A, Takala J, Djafarzadeh S, Vuda M, Dünser MV, Jakob SM. Carotid blood flow is correlated with cardiac output but not with arterial blood pressure in porcine fecal periton
Corrêa TD, Reintam Blaser A, Takala J, Djafarzadeh S, Vuda M, Dünser MV, Jakob SM (2011), 8. Corrêa TD, Reintam Blaser A, Takala J, Djafarzadeh S, Vuda M, Dünser MV, Jakob SM. Carotid blood flow is correlated with cardiac output but not with arterial blood pressure in porcine fecal periton, in Critical Care, 15(Suppl 1), S25-S25.
Effect of bacterial load vs. duration of exposure to bacteria on plasma TNF-alpha concentrations in porcine fecal peritonitis
Corrêa TD, Brander L, del Giglio A, Schröder R, Takala J, Blaser AR, Vuda M, Jakob SM (2011), Effect of bacterial load vs. duration of exposure to bacteria on plasma TNF-alpha concentrations in porcine fecal peritonitis, in Critical Care, 15(Suppl 1), S87-S88.
Impact of hepatic venous oxygen efflux and carotid blood flow on the difference between mixed and central venous oxygen saturation
Corrêa TD, Kindler R, Brandt S, Gorrasi J, Regueira T, Bracht H, Porta F, Takala J, Pearse R, Jakob SM (2011), Impact of hepatic venous oxygen efflux and carotid blood flow on the difference between mixed and central venous oxygen saturation, in Critical Care, 15(Suppl 1), S 12-S 13.
Positive central-mixed venous oxygen saturation gradients: high oxygen saturation in the inferior vena cava confirms high splanchnic oxygen extraction
Reintam Blaser A, Corrêa TD, Djafarzadeh S, Vuda M, Takala J, Dünser MV, Jakob SM (2011), Positive central-mixed venous oxygen saturation gradients: high oxygen saturation in the inferior vena cava confirms high splanchnic oxygen extraction, in Critical Care, 15(Suppl 1), S15-S15.
FLUID LOSS FROM INTRAVASCULAR SPACE OCCURS EARLY IN SEPSIS: PRELIMINARY RESULTS IN EXPERIMENTAL PORCINE PERITONITIS
Blaser AR, Correa TD, Takala J, Djafarzadeh S, Vuda M, Dunser M, Jakob SM (2010), FLUID LOSS FROM INTRAVASCULAR SPACE OCCURS EARLY IN SEPSIS: PRELIMINARY RESULTS IN EXPERIMENTAL PORCINE PERITONITIS, in INTENSIVE CARE MEDICINE, 36, 292-292.
TIME TO RESUSCITATION IN SEPSIS AND OUTCOME: A PRELIMINARY EVALUATION OF CLINICAL PATTERN, INCIDENCE OF ORGAN DYSFUNCTION AND MORTALITY IN A PORCINE MODEL OF FECAL PERITONITIS
Correa TD, Reintam A, Takala J, Siamak D, Vuda M, Dunser M, Jakob SM (2010), TIME TO RESUSCITATION IN SEPSIS AND OUTCOME: A PRELIMINARY EVALUATION OF CLINICAL PATTERN, INCIDENCE OF ORGAN DYSFUNCTION AND MORTALITY IN A PORCINE MODEL OF FECAL PERITONITIS, in INTENSIVE CARE MEDICINE, 36, 291-291.
TIME TO RESUSCITATION: EFFECTS ON MITOCHONDRIAL FUNCTION AND OUTCOME IN EXPERIMENTAL SEPSIS MODEL
Vuda M, Correa TD, Reintam A, Takala J, Jakob SM, Djafarzadeh S (2010), TIME TO RESUSCITATION: EFFECTS ON MITOCHONDRIAL FUNCTION AND OUTCOME IN EXPERIMENTAL SEPSIS MODEL, in INTENSIVE CARE MEDICINE, 36, 409-409.

Abstract

Establish a detailed research plan. Please mention the objectives and goals, the methods of investigation, the available data, the data to be collected.Summary of the research planBackground: Mortality in sepsis remains unacceptably high. While some factors predisposing to a bad outcome have bee defined, data on the impact of mitochondrial dysfunction is controversial. During sepsis, the renin-angiotensin system is activated and data is accumulating that Angiotensin-II influences mitochondrial oxygen consumption. Early treatment of sepsis with improves outcome in sepsis, but depending on treatment goals, excessive exposure to essential components of the treatment package, such as .fluids and vasopressors can be harmful. Working hypothesis: The delay between onset of sepsis and hemodynamic stabilization with vasopressors modifies mitochondrial dysfunction in sepsis. The targets of hemodynamic support influences the extent of exposure to vasopressors, and this may contribute to the severity of organ and cellular dysfunction. Sepsis per se and the hemodynamic support with exogenous vasopressors interfere with the cardiovascular control, where angiotensin-II has a central role. Our pilot experiments show that angiotensin-II influences mitochondrial oxygen consumption. We hypothesize that angiotensin-II may be an important mediator of cellular respiration in sepsis. Specific aims: To evaluate sequentially skeletal mitochondrial function during periods of different length of unresuscitated sepsis and during the subsequent treatment period in an animal model representing closely the conditions in human sepsis. To evaluate tissue perfusion and organ function, including hepatic, skeletal muscle and myocardial mitochondrial function, after resuscitation to different blood pressure goals with Angiotensin and Norepinephrine. Experimental design / methods: 32 animals will be randomized to a control group and three groups resuscitated 6, 12, and 24 hours, respectively, after fecal peritonitis induction. Resuscitation will be performed according to the SCC and ESICM sepsis guidelines for 48 hours. Systemic, carotid and femoral blood flow, right ventricular end-diastolic volume and ejection fraction., and mixed, hepatic and renal venous oxygen saturation will be measured continuously. Skeletal mitochondrial function will be assessed at baseline and after 6, 12, 24, 48 and 72 hours, when applicable, or before death occurs, if earlier. The role of the Angiotensin-II and ACE on mitochondrial function will specifically assessed in-vitro. Permebilized cellular and isolated mitochondrial respiration will be studied using high resolution respirometry. Subcellular fractionation (Western blotting) and immunogold-electron microscopy (EM) will be used to localize renin-angiotensin system components within cells and to conventional EM to reveal alterations in mitochondrial morphology. At then end of the experiment, also hepatic and myocardial mitochondrial function will be assessed, and histological analysis performed from brain, heart, lungs, liver, kidney and gut. In further experiments, another 32 animals will be randomized to a control group and three groups with fecal peritonitis resuscitated with mean arterial blood pressure targets of 50, 65, and 80 mm Hg, respectively. The time between induction of fecal peritonitis and resuscitation will be determined when the results from project A are available. The same hemodynamic monitoring and tissue analysis as in the former series will be performed. In still further experiments, 24 animals with fecal peritonitis will be resuscitated to a mean arterial pressure which will be determined from the previous project. The animals will be randomized to norepinephrine infusion with or without prior angiotensin converting enzyme inhibition, and to angiotensin infusion, respectively. The same hemodynamic monitoring and tissue analysis as in the former series will be performed.Expected value of the proposed projectThis project will give answers to what degree mitochondrial dysfunction is involved in the pathophysiology of sepsis in an experimental model which close imitates clinical conditions. Insight will be gained into the regulation of mitochondrial function by the renin-angiotensin system. Existing mitochondrial dysfunction in sepsis would offer treatment options. Further, the project will demonstrate which arterial blood pressure target preserves organ function best, and at which dosage the use of catecholamine vasopessors could eventually be harmful.
-