Sepsis is generally viewed as a disease aggravated by an inappropriate immune response encountered in the afflicted individual. As an important organ system frequently compromised by sepsis and always affected by septic shock, the cardiovascular system and its dysfunction during sepsis have been studied in clinical and basic research for more than 5 decades. Although a number of mediators and pathways have been shown to be associated with myocardial depression in sepsis, the precise cause remains unclear to date. There is currently no evidence supporting global ischemia as an underlying cause of myocardial dysfunction in sepsis; however, in septic patients with coexistent and possibly undiagnosed coronary artery disease, regional myocardial ischemia or infarction secondary to coronary artery disease may certainly occur. A circulating myocardial depressant factor in septic shock has long been proposed, and potential candidates for a myocardial depressant factor include cytokines, prostanoids, and nitric oxide, among others. Endothelial activation and induction of the coagulatory system also contribute to the pathophysiology in sepsis. Prompt and adequate antibiotic therapy accompanied by surgical removal of the infectious focus, if indicated and feasible, is the mainstay and also the only strictly causal line of therapy. In the presence of severe sepsis and septic shock, supportive treatment in addition to causal therapy is mandatory. The purpose of this review is to delineate some characteristics of septic myocardial dysfunction, to assess the most commonly cited and reported underlying mechanisms of cardiac dysfunction in sepsis, and to briefly outline current therapeutic strategies and possible future approaches.

Sepsis and the Heart

Objective:To evaluate the effects of dobutamine on microcirculatory blood flow alterations in patients with septic shock.Design:Prospective, open-label study.Setting:A 31-bed, medico-surgical intensive care unit of a university hospital.Patients:Twenty-two patients with septic shock.Interventions:In

The effects of dobutamine on microcirculatory alterations in patients with septic shock are independent of its systemic effects

Sepsis is aggravated by an inappropriate immune response to invading microorganisms, which occasionally leads to multiple organ failure. Several lines of evidence suggest that the ventricular myocardium is depressed during sepsis with features of diastolic dysfunction. Potential candidates responsible for septic cardiomyopathy include pathogen-associated molecular patterns (PAMPs), cytokines, and nitric oxide. Extracellular histones and high-mobility group box 1 that function as endogenous damage-associated molecular patterns (DAMPs) also contribute to the myocardial dysfunction associated with sepsis. If untreated, persistent shock causes cellular injury and the liberation of further DAMPs. Like PAMPs, DAMPs have the potential to activate inflammation, creating a vicious circle. Early infection control with adequate antibiotic care is important during septic shock to decrease PAMPs arising from invasive microorganisms. Early aggressive fluid resuscitation as well as the administration of vasopressors and inotropes is also important to reduce DAMPs generated by damaged cells although excessive volume loading, and prolonged administration of catecholamines might be harmful. This review delineates some features of septic myocardial dysfunction, assesses its most common underlying mechanisms, and briefly outlines current therapeutic strategies and potential future approaches.

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Sepsis-induced myocardial dysfunction: pathophysiology and management.

Cytopathic Hypoxia: Mitochondrial Dysfunction as Mechanism Contributing to Organ Dysfunction in Sepsis

Introduction
To assess changes in renal blood flow (RBF) in human and experimental sepsis, and to identify determinants of RBF.

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Renal blood flow in sepsis

Endotoxemia can affect the storage of high-energy phosphates [ATP, creatine phosphate (CrP)] even in organs in which global blood flow does not fall. If a decrease in this storage is due to an inadequate oxygen supply-to-demand ratio, improving the perfusion should restore it. Therefore, in anesthetized endotoxemic rats we studied organ perfusion and the storage of high-energy phosphates of heart, liver, kidney, and skeletal muscle and measured the effects of improving cardiac output (CO) and organ blood flow with cardiostimulatory drugs [dopexamine (DX) and dobutamine (DB)]. Endotoxin (Escherichia coli O127.B8, 8 mg/kg) was infused from 0 to 60 min in three groups of anesthetized rats: one untreated (saline only) group (ES; n = 10), and two groups in which we infused DX (3 x 10(-8) mol.kg-1.min-1; n = 10) or DB (10(-7) mol.kg-1.min-1; n = 8) from 60 to 135 min. A fourth group served as time-matched controls (C; n = 8). Organ blood flows at 0 and 135 min (end of experiment) were measured with radioactive microspheres. In biopsies (at 135 min) we measured lactate, ATP, and CrP concentrations. Endotoxemia decreased CO (45% at 135 min; P < 0.05), which could be restored by DX and DB. Myocardial and skeletal muscle blood flow and ATP did not differ in the groups at 135 min. Hepatic and renal blood flow decreased in the ES group 44 and 52%, respectively (P < 0.05); DX restored the fall of hepatic and DB of renal blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

High-energy phosphates in heart, liver, kidney, and skeletal muscle of endotoxemic rats

Renal failure often complicates endotoxin shock. This might be due to renal hypoperfusion, but endotoxemia could also have additional effects. We studied in anesthetized rats renal plasma flow (RPF), glomerular filtration rate (GFR), and metabolism (ATP, CrP = creatine phosphate, energy charge = [ATP + 0.5 ADP]/[ATP + ADP + AMP], lactate, glucose) during endotoxin shock (Escherichia coli endotoxin, 10 mg/kg for 60 min; n = 10) and "balloon shock" (balloon inflated in vena cava below renal vein to cause comparable decreases in cardiac output and RPF as in endotoxin-treated rats; n = 10). A third group of rats served as controls (n = 10). At t = 0 infusion of endotoxin was started. At t = 90 min, when cardiac output was low and serum lactate was high (indicating shock), GFR and RPF were obtained from plasma disappearance rates (from t = 90 to t = 135 min) of 125I-thalamate and 131I-hippurate, respectively. Experiments ended at t = 135 min. In both shock groups RPF decreased (by ca. - 75% compared with control rats), but filtration fraction only increased (by 72%) in the "balloon shock" rats. In renal biopsies lactate concentration increased more (by 407 vs. 167%) and ATP decreased more (by -63 vs. - 35%) during endotoxin shock than during "balloon shock"; the endotoxin-treated rats also showed a significant decrease in CrP (by - 58%), energy charge (by - 31%), and glucose concentration (by - 34%), and an increase in the number of leukocytes in the glomeruli (by 730%). Renal function and metabolism thus was more affected in this hypodynamic form of endotoxin shock than in "balloon shock." This may be caused by the effects of endotoxin on sticking of leukocytes and renal metabolism.

Renal function and metabolism during endotoxemia in rats: role of hypoperfusion.

Endotoxin shock not only causes renal failure, endotoxemia also leads to metabolic impairment, resulting in energy shortage and loss of cellular integrity; therefore, we tested the hypothesis that early changes in renal metabolism contribute to the development of acute renal failure during endotoxin shock. Endotoxin (Escherichia coli127B8; 8 mg/kg from t = 0 to 60 min) was infused in three groups of 8 rats, in which renal biopsies were taken at t = 30,50 and 90 min, respectively; a fourth group (n – 8) served as control. In the biopsies, glucose, lactate, ATP, ADP, AMP and creatine phosphate concentrations were determined. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured from the clearances of 131I-hippurate and 125I-thalamate, respectively. We also assayed urine flow (V; catheter in the bladder), cardiac output (CO), blood pressure (MAP), heart rate (HR) and arterial lactate, glucose and creatinine concentrations. During the first 30 min of endotoxemia, we found no systemic hemodynamic or biochemical changes. From t = 30 to t = 90, CO and MAP decreased to 59 and 70%, respectively, while HR and serum levels rose to 110 and 800%, respectively (p

A.A. van Kraats

Papers

High-energy phosphates in heart, liver, kidney, and skeletal muscle of endotoxemic rats

Renal function and metabolism during endotoxemia in rats: role of hypoperfusion.

Development of renal failure in endotoxemic rats : can it be explained by early changes in renal energy metabolism ?

Systemic and renal actions of dopexamine and dobutamine during endotoxin shock in the rat