Sepsis leads to a complex intramyocardial inflammatory response that results in sepsis-induced myocardial dysfunction. Here, recent findings are reviewed in a physiologic context.
Decreased systolic ...contractility during sepsis limits ventricular ejection and stroke volume. Initially, this effect is compensated for by increased diastolic filling during volume resuscitation. Reduced afterload due to arterial vasodilation also compensates so that cardiac output can be maintained or increased. Recent results recognize the importance of diastolic dysfunction, reduced ventricular diastolic compliance that impedes ventricular filling. Diastolic dysfunction becomes increasingly important as severity of septic shock increases. When impaired ventricular ejection is coupled with limited diastolic filling, stroke volume must decrease. Accordingly, diastolic dysfunction is more closely related to mortality than systolic dysfunction. Recent trials of beta-adrenergic agonists and levosimendan have been disappointing, while approaches to modulating the intramyocardial inflammatory response show promise.
Sepsis-induced myocardial dysfunction is increasingly recognized as a major contributor to outcome of septic shock. Significant strides have been made in understanding the intramyocardial inflammatory response that causes myocardial dysfunction. A number of novel approaches show promise by modulating the intramyocardial inflammatory response.
Increased blood lactate concentration (hyperlactatemia) and lactic acidosis (hyperlactatemia and serum pH < 7.35) are common in patients with severe sepsis or septic shock and are associated with ...significant morbidity and mortality. In some patients, most of the lactate that is produced in shock states is due to inadequate oxygen delivery resulting in tissue hypoxia and causing anaerobic glycolysis. However, lactate formation during sepsis is not entirely related to tissue hypoxia or reversible by increasing oxygen delivery. In this review, we initially outline the metabolism of lactate and etiology of lactic acidosis; we then address the pathophysiology of lactic acidosis in sepsis. We discuss the clinical implications of serum lactate measurement in diagnosis, monitoring, and prognostication in acute and intensive care settings. Finally, we explore treatment of lactic acidosis and its impact on clinical outcome.
Many aspects of left ventricular function are explained by considering ventricular pressure-volume characteristics. Contractility is best measured by the slope, Emax, of the end-systolic ...pressure-volume relationship. Ventricular systole is usefully characterized by a time-varying elastance (ΔP/ΔV). An extended area, the pressure-volume area, subtended by the ventricular pressure-volume loop (useful mechanical work) and the ESPVR (energy expended without mechanical work), is linearly related to myocardial oxygen consumption per beat. For energetically efficient systolic ejection ventricular elastance should be, and is, matched to aortic elastance. Without matching, the fraction of energy expended without mechanical work increases and energy is lost during ejection across the aortic valve. Ventricular function curves, derived from ventricular pressure-volume characteristics, interact with venous return curves to regulate cardiac output. Thus, consideration of ventricular pressure-volume relationships highlight features that allow the heart to efficiently respond to any demand for cardiac output and oxygen delivery.
The use of pulmonary artery catheters has diminished, so that other technologies are emerging. Central venous oxygen saturation measurement (ScvO₂) as a surrogate for mixed venous oxygen saturation ...measurement (SvO₂) is simple and clinically accessible. To maximize the clinical utility of ScvO₂ (or SvO₂) measurement, it is useful to review what the measurement means in a physiologic context,how the measurement is made, important limitations, and how this measurement may be helpful in common clinical scenarios. Compared with cardiac output measurement, SvO₂ is more directly related to tissue oxygenation. Furthermore,when tissue oxygenation is a clinical concern, SvO₂ is less prone to error compared with cardiac output, where small measurement errors may lead to larger errors in interpreting adequacy of oxygen delivery. ScvO₂ should be measured from the tip of a central venous catheter placed close to, or within, the right atrium to reduce measurement error. Correct clinical interpretation of SvO₂, or its properly measured ScvO₂ surrogate, can be used to (1) estimate cardiac output using the Fick equation, (2) better understand whether a patient's oxygen delivery is adequate to meet their oxygen demands, (3) help guide clinical practice, particularly when resuscitating patients using validated early goal directed therapy treatment protocols, (4) understand and treat arterial hypoxemia, and (5) rapidly estimate shunt fraction (venous admixture).
OBJECTIVE:HDL (high-density lipoprotein) cholesterol (HDL-C) and LDL (low-density lipoprotein) cholesterol (LDL-C) are inversely associated with infectious hospitalizations. Whether these represent ...causal relationships is unknown.
APPROACH AND RESULTS:Adults of 40 to 69 years of age were recruited from across the United Kingdom between 2006 and 2010 and followed until March 31, 2016, as part of the UK Biobank. We determined HDL-C, LDL-C, and triglyceride polygenic scores for UK Biobank participants of British white ancestry (n=407 558). We examined the association of lipid levels and polygenic scores with infectious hospitalizations, antibiotic usage, and 28-day sepsis survival using Cox proportional hazards or logistic regression models. Measured levels of HDL-C and LDL-C were inversely associated with risk of infectious hospitalizations, while triglycerides displayed a positive association. A 1-mmol/L increase in genetically determined levels of HDL-C associated with a hazard ratio for infectious disease of 0.84 (95% CI, 0.75–0.95; P=0.004). Mendelian randomization using genetic variants associated with HDL-C as an instrumental variable was consistent with a causal relationship between elevated HDL-C and reduced risk of infectious hospitalizations (inverse weighted variance method, P=0.001). Furthermore, of 3222 participants who experienced an index episode of sepsis, there was a significant inverse association between continuous HDL-C polygenic score and 28-day mortality (adjusted hazard ratio, 0.37 95% CI, 0.14–0.96 per 1 mmol/L increase; P=0.04). LDL-C and triglyceride polygenic scores were not significantly associated with hospitalization for infection, antibiotic use, or sepsis mortality.
CONCLUSIONS:Our results provide causal inference for an inverse relationship between HDL-C, but not LDL-C or triglycerides, and risk of an infectious hospitalization.
Sepsis is the leading cause of death in critically ill patients. While decreased Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) function improves clinical outcomes in murine and human sepsis, ...the mechanisms involved have not been fully elucidated. We tested the hypothesis that lipopolysaccharide (LPS), the major Gram-negative bacteria endotoxin, is cleared from the circulation by hepatocyte Low Density Lipoprotein Receptors (LDLR)-receptors downregulated by PCSK9. We directly visualized LPS uptake and found that LPS is rapidly taken up by hepatocytes into the cell periphery. Over the course of 4 hours LPS is transported towards the cell center. We next found that clearance of injected LPS from the blood was reduced substantially in Ldlr knockout (Ldlr-/-) mice compared to wild type controls and, simultaneously, hepatic uptake of LPS was also reduced in Ldlr-/- mice. Specifically examining the role of hepatocytes, we further found that primary hepatocytes isolated from Ldlr-/- mice had greatly decreased LPS uptake. In the HepG2 immortalized human hepatocyte cell line, LDLR silencing similarly resulted in decreased LPS uptake. PCSK9 treatment reduces LDLR density on hepatocytes and, therefore, was another independent strategy to test our hypothesis. Incubation with PCSK9 reduced LPS uptake by hepatocytes. Taken together, these findings demonstrate that hepatocytes clear LPS from the circulation via the LDLR and PCSK9 regulates LPS clearance from the circulation during sepsis by downregulation of hepatic LDLR.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Walley discusses the causal mechanistic pathways in sepsis-associated acute respiratory distress syndrome (ARDS). He cites the study by Jones and colleagues that uncovers the link of the soluble ...receptor for advanced glycation end products (sRAGE) and blood levels to sepsis-ARDS. He is also critical on the claims of the authors of the study that sRAGE causally contributes to sepsis-associated ARDS where such is an important step to take, for multiple reasons.
OBJECTIVE:To determine whether central venous pressure and fluid balance after resuscitation for septic shock are associated with mortality.
DESIGN:We conducted a retrospective review of the use of ...intravenous fluids during the first 4 days of care.
SETTING:Multicenter randomized controlled trial.
PATIENTS:The Vasopressin in Septic Shock Trial (VASST) study enrolled 778 patients who had septic shock and who were receiving a minimum of 5 μg of norepinephrine per minute.
INTERVENTIONS:None.
MEASUREMENTS AND MAIN RESULTS:Based on net fluid balance, we determined whether oneʼs fluid balance quartile was correlated with 28-day mortality. We also analyzed whether fluid balance was predictive of central venous pressure and furthermore whether a guideline-recommended central venous pressure of 8–12 mm Hg yielded a mortality advantage. At enrollment, which occurred on average 12 hrs after presentation, the average fluid balance was +4.2 L. By day 4, the cumulative average fluid balance was +11 L. After correcting for age and Acute Physiology and Chronic Health Evaluation II score, a more positive fluid balance at both at 12 hrs and day 4 correlated significantly with increased mortality. Central venous pressure was correlated with fluid balance at 12 hrs, whereas on days 1–4, there was no significant correlation. At 12 hrs, patients with central venous pressure <8 mm Hg had the lowest mortality rate followed by those with central venous pressure 8–12 mm Hg. The highest mortality rate was observed in those with central venous pressure >12 mm Hg. Contrary to the overall effect, patients whose central venous pressure was <8 mm Hg had improved survival with a more positive fluid balance.
CONCLUSIONS:A more positive fluid balance both early in resuscitation and cumulatively over 4 days is associated with an increased risk of mortality in septic shock. Central venous pressure may be used to gauge fluid balance ≤12 hrs into septic shock but becomes an unreliable marker of fluid balance thereafter. Optimal survival in the VASST study occurred with a positive fluid balance of approximately 3 L at 12 hrs.
A decrease in the activity of proprotein convertase subtilisin/kexin type 9 (PCSK9) increases the amount of low-density lipoprotein (LDL) receptors on liver cells and, therefore, LDL clearance. The ...clearance of lipids from pathogens is related to endogenous lipid clearance; thus, PCSK9 may also regulate removal of pathogen lipids such as lipopolysaccharide (LPS). Compared to controls, Pcsk9 knockout mice displayed decreases in inflammatory cytokine production and in other physiological responses to LPS. In human liver cells, PCSK9 inhibited LPS uptake, a necessary step in systemic clearance and detoxification. Pharmacological inhibition of PCSK9 improved survival and inflammation in murine polymicrobial peritonitis. Human PCSK9 loss-of-function genetic variants were associated with improved survival in septic shock patients and a decrease in inflammatory cytokine response both in septic shock patients and in healthy volunteers after LPS administration. The PCSK9 effect was abrogated in LDL receptor (LDLR) knockout mice and in humans who are homozygous for an LDLR variant that is resistant to PCSK9. Together, our results show that reduced PCSK9 function is associated with increased pathogen lipid clearance via the LDLR, a decreased inflammatory response, and improved septic shock outcome.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a recent high-impact cardiovascular intervention aimed at reducing low-density lipoprotein (LDL) cholesterol levels. Notably, ...pathogen lipids are also carried in lipoprotein particles and are cleared by hepatocyte LDL receptors. Therefore, the role of PCSK9 in sepsis is reviewed.
Endogenous PCSK9 decreases clearance of LDL cholesterol by decreasing the number of LDL receptors on hepatocytes. Similarly, PCSK9 decreases clearance of pathogen lipids, such as endotoxin, carried in LDL. Pathogen lipids, such as lipopolysaccharide (LPS) from gram-negative organisms or lipoteichoic acid from gram-positive organisms, are carried in high-density lipoprotein, LDL, and very low-density lipoprotein particles. Transfer proteins that handle pathogen lipids (e.g., LPS binding protein) are homologous to transfer proteins that handle cholesterol (e.g., phospholipid transfer protein, cholesterol ester transfer protein). Reduction in PCSK9 function results in increased LPS clearance, a decreased inflammatory response, and improved clinical outcomes in mice. PCSK9 inhibition improves survival in septic mice. Similarly, humans who carry loss-of-function variants of the PCSK9 gene have increased survival in sepsis.
PCSK9 inhibition may be a useful strategy to increase pathogen lipid clearance in the treatment of patients with sepsis.
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