Myocardial dysfunction in septic shock

Over the last decade, it has become clear that myocardial depression, like vascular dysfunction, is typical of human septic shock. Human septic myocardial depression is characterized by reversible biventricular dilatation, decreased ejection fraction, and decreased response to fluid resuscitation and catecholamine stimulation (in the presence of overall hyperdynamic circulation). A circulating myocardial depressant substance, not myocardial hypoperfusion, is responsible for this phenomenon. This substance has been shown to represent low concentrations of TNF-alpha and IL-1 beta acting in synergy on the myocardium through mechanisms that include NO and cGMP generation. Despite major advances in our understanding of the hemodynamics and pathogenesis of cardiac dysfunction in sepsis, successful attempts to modulate these mechanisms to improve clinical outcomes in human trials have not been demonstrated to date. For the moment, the therapeutic approach to the patient with cardiac dysfunction in distributive or septic shock must be primarily aimed at reestablishing adequate organ perfusion and oxygen delivery by vigorous fluid resuscitation and vasopressor or inotropic support. In the long term, however, only continued research regarding the cellular mechanisms of organ dysfunction, including septic myocardial depression, will lead to successful therapeutic strategies. These strategies will likely involve direct manipulation of intracellular signaling processes that lead to organ dysfunction as manifested by septic myocardial dysfunction and septic shock.     

Clinical spectrum, frequency, and significance of myocardial dysfunction in severe sepsis and septic shock

ObjectiveTo determine the frequency and spectrum of myocardial dysfunction in patients with severe sepsis and septic shock using transthoracic echocardiography and to evaluate the impact of the myocardial dysfunction types on mortality.Patients and MethodsA prospective study of 106 patients with severe sepsis or septic shock was conducted from August 1, 2007, to January 31, 2009. All patients underwent transthoracic echocardiography within 24 hours of admission to the intensive care unit. Myocardial dysfunction was classified as left ventricular (LV) diastolic, LV systolic, and right ventricular (RV) dysfunction. Frequency of myocardial dysfunction was calculated, and demographic, hemodynamic, and physiologic variables and mortality were compared between the myocardial dysfunction types and patients without cardiac dysfunction.ResultsThe frequency of myocardial dysfunction in patients with severe sepsis or septic shock was 64% (n=68). Left ventricular diastolic dysfunction was present in 39 patients (37%), LV systolic dysfunction in 29 (27%), and RV dysfunction in 33 (31%). There was significant overlap. The 30-day and 1-year mortality rates were 36% and 57%, respectively. There was no difference in mortality between patients with normal myocardial function and those with left, right, or any ventricular dysfunction.ConclusionMyocardial dysfunction is frequent in patients with severe sepsis or septic shock and has a wide spectrum including LV diastolic, LV systolic, and RV dysfunction types. Although evaluation for the presence and type of myocardial dysfunction is important for tailoring specific therapy, its presence in patients with severe sepsis and septic shock was not associated with increased 30-day or 1-year mortality.     

Cardiac troponin: a new serum marker of myocardial injury in sepsis

Objective: Echocardiogram-derived left ventricular ejection fraction (LVEF) is usually utilized to evaluate left ventricular function, including that of septic patients. However, LVEF is greatly influenced by afterload. The aim of this study was to test the hypothesis that troponin I, a serum marker of myocardial injury, may be able to detect left ventricular involvement by the septic process, being at least as sensitive an indicator of left ventricular dysfunction as LVEF in these patients.¶Design: Comparison of echocardiogram-derived LVEF with serum levels of troponin I in ten critically ill septic patients.¶Setting: General intensive care unit in a tertiary care private hospital.¶Patients: Ten critically ill septic patients with no previous documented heart disease.¶Measurements and results: Patients were simultaneously submitted to a two-dimensional echocardiogram and troponin I determinations. LVEFs and troponin I levels were analyzed in a two-by-two table in order to validate troponin I as a new biochemical marker of myocardial injury in sepsis. All the patients whose LVEF was < 0.5 had elevated troponin I levels (kappa = 0.61, p = 0.035).¶Conclusions: Identification of myocardial dysfunction in septic patients has been a challenging task. Troponin I, a serum marker of myocardial injury, may be of great help in the recognition of myocardial involvement by sepsis in a noninvasive and readily available way.     

Sepsis and myocardial depression in a young woman

Severe sepsis may be associated with depression of myocardial function, attributed to various inflammatory mediators. Myocardial dysfunction in sepsis is characterized by biventricular failure and complicates usual therapy with high-volume fluid resuscitation and vasopressors. However, in patients who survive septic shock, myocardial dysfunction can improve rapidly. We describe a young woman with septic shock due to Streptococcus pneumoniae, complicated by severe but reversible biventricular dysfunction.     

Clinical review: Myocardial depression in sepsis and septic shock

Myocardial dysfunction frequently accompanies severe sepsis and septic shock. Whereas myocardial depression was previously considered a preterminal event, it is now clear that cardiac dysfunction as evidenced by biventricular dilatation and reduced ejection fraction is present in most patients with severe sepsis and septic shock. Myocardial depression exists despite a fluid resuscitation-dependent hyperdynamic state that typically persists in septic shock patients until death or recovery. Cardiac function usually recovers within 7-10 days in survivors. Myocardial dysfunction does not appear to be due to myocardial hypoperfusion but due to circulating depressant factors, including the cytokines tumor necrosis factor alpha and IL-1beta. At a cellular level, reduced myocardial contractility seems to be induced by both nitric oxide-dependent and nitric oxide-independent mechanisms. The present paper reviews both the clinical manifestations and the molecular/cellular mechanisms of sepsis-induced myocardial depression.     

Myocardial dysfunction in the patient with sepsis

The nature of myocardial dysfunction during sepsis and septic shock has been investigated for more than half a century. This review traces the evolution of scientific thought regarding this phenomenon during this period with particular emphasis on the current understanding of both the clinical manifestations and the molecular/cellular basis of septic myocardial dysfunction in critically ill patients. Current data suggest, contrary to older literature, that patients with septic shock develop a hyperdynamic circulatory state after fluid resuscitation and maintain this hyperdynamic circulatory state until death or recovery. Overt myocardial depression, as manifested by decreased cardiac output, is decidedly uncommon, even in the preterminal phase. Nonetheless, myocardial depression, as evidenced by biventricular dilation and depression of the ejection fraction, can be demonstrated in most patients with septic shock by using either radionuclide cineangiography or echocardiography. Depression is reversible over the course of 7 to 10 days in survivors. Available evidence suggests that myocardial hypoperfusion is not responsible for septic myocardial depression, because examination of humans with septic shock demonstrates increased myocardial perfusion, and animal models of septic shock appear to maintain myocardial high-energy phosphates. A circulating factor or factors, including the cytokines tumor necrosis factor alpha and interleukin-1beta, appear to have a significant role in the phenomenon. In addition, septic myocardial depression appears to be mediated in part through combinations of nitric oxide-dependent and -independent alterations of basal and catecholamine-stimulated cardiac myocyte contractility.     

Septic acute kidney injury: new concepts

Acute kidney injury (AKI) is a serious condition that affects many ICU patients. The most common causes of AKI in ICU are severe sepsis and septic shock. The mortality of AKI in septic critically ill patients remains high despite of our increasing ability to support vital organs. This is partly due to our poor understanding of the pathogenesis of sepsis-induced renal dysfunction. However, new concepts are emerging to explain the pathogenesis of septic AKI, which challenge previously held dogma. Throughout the past half century, septic AKI has essentially been considered secondary to kidney ischemia. However, recent models of experimental sepsis have challenged this notion by demonstrating that, in experimental states, which simulate the hemodynamic picture most typically seen in man (e.g. hyperdynamic sepsis) renal blood flow, actually increases as renal vascular resistance decreases. These experimental observations provide proof of concept that septic AKI can occur in the setting of renal hyperemia and that ischemia is not necessary for loss of glomerular filtration rate (GFR) to occur. They also suggest that similar hemodynamic event may occur in man. In addition, preliminary studies in septic sheep show that, when ATP is measured using an implanted phosphorus coil and magnetic resonance technology, renal bioenergetics are preserved in the setting of advanced septic shock. While these findings need to be confirmed, they challenge established paradigms and offer a new conceptual framework of reference for further investigation and intervention in man.     

Clinical review: Hypertonic saline resuscitation in sepsis

The present review discusses the hemodynamic effects of hypertonic saline in experimental shock and in patients with sepsis. We comment on the mechanisms of action of hypertonic saline, calling upon data in hemorrhagic and septic shock. Specific actions of hypertonic saline in severe sepsis and septic shock are highlighted. Data are available that support potential benefits of hypertonic saline infusion in various aspects of the pathophysiology of sepsis, including tissue hypoperfusion, decreased oxygen consumption, endothelial dysfunction, cardiac depression, and the presence of a broad array of proinflammatory cytokines and various oxidant species. The goal of research in this field is to identify reliable therapies to prevent ischemia and inflammation, and to reduce mortality.     

Comparable increase of B-type natriuretic peptide and amino-terminal pro-B-type natriuretic peptide levels in patients with severe sepsis, septic shock, and acute heart failure

OBJECTIVE: B-type natriuretic peptide (BNP) and N-terminal pro-BNP measurements are used for the diagnosis of congestive heart failure (HF). However, the diagnostic value of these tests is unknown under septic conditions. We compared patients with severe sepsis or septic shock and patients with acute HF to unravel the influence of the underlying diagnosis on BNP and N-terminal pro-BNP levels. DESIGN: Prospective, clinical study. SETTING: Academic medical intensive care unit (ICU). PATIENTS: A total of 249 consecutive patients were screened for the diagnosis of sepsis or HF. Sepsis was defined according to published guidelines. HF was diagnosed in the presence of an underlying heart disease and congestive HF, pulmonary edema, or cardiogenic shock. INTERVENTIONS: BNP and N-terminal pro-BNP were measured from blood samples that were drawn daily for routine analysis. MEASUREMENTS AND MAIN RESULTS: We identified 24 patients with severe sepsis or septic shock and 51 patients with acute HF. At admission, the median (range) BNP and N-terminal pro-BNP levels were 572 (13-1,300) and 6,526 (198-70,000) ng/L in patients with sepsis and 581 (6-1,300) and 4,300 (126-70,000) ng/L in patients with HF. The natriuretic peptide levels increased during the ICU stay, but the differences between the groups were not significant. Nine patients with sepsis and eight patients with HF were monitored with a pulmonary artery catheter. Mean (sd) pulmonary artery occlusion pressure were 16 (4.2) and 22 (5.3) mm Hg (p = .02), and cardiac indexes were 4.6 (2.8) and 2.2 (0.6) L/min/m (p = .03) in patients with sepsis and HF, respectively. Despite these clear hemodynamic differences BNP and N-terminal pro-BNP levels were not statistically different between the two groups. CONCLUSION: In patients with severe sepsis or septic shock, BNP and N-terminal pro-BNP values are highly elevated and, despite significant hemodynamic differences, comparable with those found in acute HF patients. It remains to be determined how elevations of natriuretic peptide levels are linked to inflammation and sepsis-associated myocardial dysfunction.     

Effects of acid base disturbance, septic shock, and calcium and phosphorous abnormalities on cardiovascular function

Systemic acidosis has a negative inotropic effect on myocardial function, which in the intact animal, is counteracted by the activation of the sympathoadrenal system. Although there are extensive animal data in this field, human studies quantifying the influence of systemic acidosis on myocardial function in various disease states is lacking. In patients with hypocalcemia, a single infusion of calcium does not sustain increased calcium levels, and the hemodynamic improvement is only transient. Hemodynamic changes in septic shock are complex, and there are convincing data documenting myocardial dysfunction in sepsis. There is a need for elucidating the biochemical characteristics of the myocardial depressant factor (or factors).     

Myocardial dysfunction in sepsis

The characteristic hemodynamic profile of human septic shock consists of a normal or elevated cardiac index and a decreased systemic vascular resistance index. When a patient with septic shock has a low cardiac index, concomitant hypovolemia is usually present. Within 48 hours of the onset of septic shock, most patients develop marked dilatation of both ventricles, depressed ejection fractions, and alterations of the Frank-Starling and diastolic pressure-volume relationships; stroke volume typically is well maintained. In surviving patients, cardiac function returns to normal within 10 days. An identical sequence of hemodynamic abnormalities occurs in an experimental canine model of sepsis that employs intraperitoneal implantation of infected fibrin clots. This myocardial dysfunction is not due to global myocardial ischemia; instead, there appear to be one or more circulating myocardial depressant substances. The chemical nature of these circulation mediators is under intensive investigation clinically, in vitro, and in the canine model.     

Oxygen consumption in sepsis and septic shock

This review article examines the pathophysiology of septic shock, with special attention to the concept of supply-dependent consumption and the implications this concept has for therapy. Patients with septic shock require higher levels of oxygen delivery (DO2) to maintain aerobic metabolism. When DO2 is inadequate, peripheral tissues switch to anaerobic metabolism and oxygen consumption decreases. The lactic acidosis that occurs is a reasonable clinical marker of supply dependency and inadequate tissue perfusion. Maximizing DO2 is an important part of the hemodynamic resuscitation of patients with septic shock. To achieve this goal, intravascular volume must be restored and the myocardial depression associated with sepsis must be treated to optimize cardiac output. The normalization of arterial lactate concentration is a reasonable goal of resuscitative efforts.     

Impaired sarcoplasmic calcium release inhibits myocardial contraction in experimental sepsis

PURPOSE: In septic shock, myocardial dysfunction develops over the course of illness, but the mechanism of this depression is not clear. In this study, mechanisms of myocardial dysfunction were examined in a porcine model of Escherichia coli sepsis. MATERIALS AND METHODS: Animals were subjected to 4 hours of bacteria infusion (n = 5) (septic group) or saline infusion (n = 5) (nonseptic group), after which trabeculae were removed from the right ventricle and placed into a recirculating water bath. Measurements of steady-state contraction (SSC) were obtained at 0.5, 1, and 2 Hz. Indirect indices were used to assess abnormalities in myocardial calcium metabolism in sepsis. Extrasystoles (ES) were used to assess transsarcolemmal (TSL) calcium flux and were measured at 300 milliseconds, 400 milliseconds, and 500 milliseconds after the preceding stimulus. Postrest contraction (PRC) is an indicator of SR recirculation from the uptake to the release site and was obtained after interposing intervals of rest between steady-state beats at 0.5 Hz. Rapid-cooling contracture (RCC) is an indicator of sarcoplasmic reticulum (SR) content and was obtained at 0.5, 1, and 2 Hz and after interposing intervals of rest at 0.5 Hz. RESULTS: SSC was not different between groups at 0.5 Hz, but compared with the nonseptic group, SSC decreased at 1 and 2 Hz in the septic group (P < .05). PRC and TSL were not different between groups. During rest intervals, calcium leaks out of SR through the ryanodine channel (ie, SR calcium release channel). In the septic group, as assessed by RCC, SR calcium leak was less than that found in the nonseptic group. CONCLUSION: These results indicate that myocardial dysfunction in sepsis is frequency dependent, and that the mechanism is most likely caused by inhibition of SR calcium release owing to blockade of the ryanodine channel.     

Brain natriuretic peptide: A marker of myocardial dysfunction and prognosis during severe sepsis

OBJECTIVE: To investigate the value of brain natriuretic peptide plasma levels as a marker of systolic myocardial dysfunction during severe sepsis and septic shock. DESIGN: Prospective observational study. SETTING: Intensive care unit. PATIENTS: A total of 34 consecutive patients with severe sepsis (nine patients) or septic shock (25 patients) without previous cardiac, respiratory, or chronic renal failure. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Myocardial systolic performance was assessed by fractional area contraction (FAC) using echocardiography performed on days 2 (FACD2) and 8. Plasma levels of brain natriuretic peptide were measured at days 1-4 and 8 after the beginning of severe sepsis. Among 34 patients (Simplified Acute Physiology Score II, 43 +/- 2.5), 15 (44%) presented with initial myocardial dysfunction (FACD2 < 50%). Lungs were the origin of sepsis in 65% of patients. The 28-day mortality was 29%. Comparisons were performed between patients with (FACD2 < 50%) and without (FACD2 > or = 50%) myocardial dysfunction. Plasma levels of brain natriuretic peptide were significantly higher in patients with FACD2 < 50% than in those with FACD2 > or = 50% (p <.05) from day 2 to day 4. Brain natriuretic peptide levels were also significantly higher on days 2 and 3 in patients who died during their intensive care unit stay (p <.05). CONCLUSIONS: Systolic myocardial dysfunction is present in 44% of patient with severe sepsis or septic shock. In this setting, brain natriuretic peptide seems useful to detect myocardial dysfunction, and high plasma levels appear to be associated with poor outcome of sepsis, but further studies are needed.     

Therapeutic options to improve the microcirculation in sepsis and septic shock

The severe impairment of the microcirculation plays a substantial role in the pathogenesis of severe sepsis and septic shock, and leads to multiple organ failure and death. Therapeutic strategies to resuscitate the microcirculatory blood flow and to improve the functional capillar density are therefore essential to surmount the microcirculatory pathology and to avoid tissue hypoxia. Based on reasonable scientific evidence, early fluid resuscitation directed by defined haemodynamic and metabolic goals (EGDT) as well as the application of activated protein C (rhAPC) according to the guidelines could be recommended. Dobutamine is the first choice to improve cardiac output and to overcome myocardial depression in septic shock whereas phosphodiesterase-III-inhibitors and levosimendane are still experimental options. Furthermore selective inhibitors of iNOS, nitroglycerol, as well as vasopressin have to be investigated relating to their specific effects on the microcirculation and their influence on survival in seevere sepsis and septic shock.     

Cardiac troponins I and T are biological markers of left ventricular dysfunction in septic shock

BACKGROUND: Cardiac depression in severe sepsis and septic shock is characterized by left ventricular (LV) failure. To date, it is unclear whether clinically unrecognized myocardial cell injury accompanies, causes, or results from this decreased cardiac performance. We therefore studied the relationship between cardiac troponin I (cTnI) and T (cTnT) and LV dysfunction in early septic shock. METHODS: Forty-six patients were consecutively enrolled, fluid-resuscitated, and treated with catecholamines. Cardiac markers were measured at study entry and after 24 and 48 h. LV function was assessed by two-dimensional transesophageal echocardiography. RESULTS: Increased plasma concentrations of cTnI (>/=0.4 microgram/L) and cTnT (>/=0.1 microgram/L) were found in 50% and 36%, respectively, of the patients at one or more time points. cTnI and cTnT were significantly correlated (r = 0.847; P <0.0001). Compared with cTnI-negative patients, cTnI-positive subjects were older, presented higher Acute Physiology and Chronic Health Evaluation II scores at diagnosis, and tended to have a worse survival rate and a more frequent history of arterial hypertension or previous myocardial infarction. In contrast, the two groups did not differ in type of infection or pathogen, or in dose and type of catecholamine administered. Continuous electrocardiographic monitoring in all patients and autopsy in 12 nonsurvivors did not disclose the occurrence of acute ischemia during the first 48 h of observation. LV dysfunction was strongly associated with cTnI positivity (78% vs 9% in cTnI-negative patients; P <0.001). In multiple regression analysis, both cTnI and cTnT were exclusively associated with LV dysfunction (P <0.0001). CONCLUSIONS: These findings suggest that in septic shock, clinically unrecognized myocardial cell injury is a marker of LV dysfunction. The latter condition tends to occur more often in severely ill older patients with underlying cardiovascular disease. Further studies are needed to determine the extent to which myocardial damage is a cause or a consequence of LV dysfunction.     

N,N'-diacetylchitobiose, an inhibitor of lysozyme, reverses myocardial depression and lessens norepinephrine requirements in Escherichia coli sepsis in dogs

Cardiovascular dysfunction in septic shock (SS) is ascribed to the release of inflammatory mediators. Norepinephrine (NE) is often administered to treat low MAP in SS. We recently found that lysozyme c (Lzm-S) released from leukocytes was a mediator of myocardial depression in an Escherichia coil model of SS in dogs. This effect can be blocked in an in vitro preparation by chitobiose, a competitive inhibitor of Lzm-S. In the present study, we examined whether chitobiose treatment can reverse myocardial depression and obviate NE requirements in two respective canine E. coli preparations. In a 6-h study, we administered chitobiose after 3.5 h of E. coli bacteremia and compared stroke work (SW) and MAP at 6 h with a sepsis control group. In a 12-h study, we determined whether chitobiose treatment can reduce the need for NE requirements during 12 h of bacteremia. In the latter study, either chitobiose or NE was given when MAP decreased approximately 20% from the presepsis value in respective groups. In anesthetized, mechanically ventilated dogs, we monitored hemodynamic parameters during continuous E. coli infusion. In the 6-h study, chitobiose improved SW and MAP at the 6-h period as compared with the nontreated sepsis group. In the 12-h study, SW and MAP increased after chitobiose without the necessity of NE administration. These results suggest that inhibitors of Lzm-S such as chitobiose may improve myocardial depression and reduce the need for NE requirements in SS.     

Structural changes of the heart during severe sepsis or septic shock

Cardiovascular dysfunction is common in severe sepsis or septic shock. Although functional alterations are often described, the elevated serum levels of cardiac proteins and autopsy findings of myocardial immune cell infiltration, edema, and damaged mitochondria suggest that structural changes to the heart during severe sepsis and septic shock may occur and may contribute to cardiac dysfunction. We explored the available literature on structural (versus functional) cardiac alterations during experimental and human endotoxemia and/or sepsis. Limited data suggest that the structural changes could be prevented, and myocardial function improved by (pre-)treatment with platelet-activating factor, cyclosporin A, glutamine, caffeine, simvastatin, or caspase inhibitors.     

成人严重感染与感染性休克血流动力学监测及支持指南(草案)

严重感染(severe sepsis)及其相关的感染性休克(septic shock)和多器官功能障碍综合征(multiple organ dysfunction syndrome,MODS)是当前重症加强治疗病房(ICU)的主要死亡原因,也是当代重症医学面临的主要焦点及难点。在美国,每年有75万的严重感染病例发生,超过了充血性心力衰竭或乳腺癌、结肠癌和艾滋病的患病数总和,病死率在20%～63%左右,与急性心肌梗死的院外病死率相近,而且患病率以每年1.5%的比例增长,预计到2010年和2020年,严重感染的患病人数将达到93万和110万。美国每年的相关治疗     

Diastolic malfunction in sepsis and septic shock

The onset and development of cardiac insufficiency is associated with diverse pathophysiological mechanisms with attention being focused recently on studying the significance of "proinflammatory" cytokines, primarily, of TNFalpha. Fifty-nines patients (age--18-24, body weight--54-76) with sepsis (19 persons, group 1), severe sepsis (20 persons, group 2) and with septic shock (20 persons, group 3) were examined. The mechanic function of the left cardiac ventricle and hemodynamic parameters were evaluated by a routine scheme in the modes of 1D (M-echo-cardiography) and sector scanning (2D echo-cardiography) at the SIM-5000 device (Italy). The central hemodynamic indices were investigated by integral tetrapolar rheography according to Tishchenko. The results denote a big significance of diastolic malfunction of the left cardiac ventricle or "rigid" myocardium in shaping of myocardial malfunction as observed in sepsis and septic shock.