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 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.     

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.     

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.     

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.     

Myocardial depression in sepsis: From pathogenesis to clinical manifestations and treatment

The cardiovascular system plays a key role in sepsis, and septic myocardial depression is a common finding associated with increased morbidity and mortality. Myocardial depression during sepsis is not clearly defined, but it can perhaps be best described as a global (systolic and diastolic) dysfunction of both the left and right sides of the heart. The pathogenesis of septic myocardial depression involves a complex mix of systemic (hemodynamic) factors and genetic, molecular, metabolic, and structural alterations. Pulmonary artery catheterization and modern echo-Doppler techniques are important diagnostic tools in this setting. There are no specific therapies for septic myocardial depression, and the cornerstone of management is control of the underlying infectious process (adequate antibiotic therapy, removal of the source) and hemodynamic stabilization (fluids, vasopressor and inotropic agents). In this review, we will summarize the pathogenesis, diagnosis, and treatment of myocardial depression in sepsis. Additional studies are needed in order to improve diagnosis and identify therapeutic targets in septic myocardial dysfunction.     

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.     

Myocardial structural changes in long-term human severe sepsis/septic shock may be responsible for cardiac dysfunction

The present investigation sought to determine the cellular mechanisms directly dependent on long-term severe sepsis/septic shock that could lead to myocardial structural changes in humans. Human hearts from eight cases of long-term severe sepsis/septic shock arising from infection, as defined by the ACCP/SCCM Consensus Conference; eight cases of acute necrotizing pancreatitis and acute lung injury, a noninfectious pathologic cause of systemic inflammatory response; and three cases of accidental death without thoracic injury selected from autopsies were studied. Transmural blocks of myocardial tissue were excised from the middle portion of the left ventricular free wall and were fixed in formalin or were frozen. Histochemical and immunohistochemical methods were used to evaluate the cross-striations of the myocardial cells, the number and size of interstitial macrophages, the intracardiomyocyte accumulation of lipid, the actin/myosin contractile apparatus, and the expression of iNOS, nitrotyrosine, and TNF-alpha in the myocardia of septic and control hearts. Greater interstitial cellular infiltration composed of larger and elongated macrophages and TNF-alpha protein expression in myofibers, interstitial macrophage cell types, and smooth muscle cells and endothelial cell in the vessels; intracardiomyocyte lipid accumulation; scattered foci of actin/myosin contractile apparatus disruption; and increased expression for iNOS and nitrotyrosine in myocytes and interstitial macrophage cell types could be observed in long-term human septic myocardium as compared with normal and acute pancreatitis control myocardia. These findings give support to an opinion that structural changes could be responsible for long-term sepsis-induced myocardial dysfunction. The higher number of macrophages, most of them with morphological features of "activation," and TNF-alpha protein expression could favor the reduction of cardiac function in septic hearts. The intramyocyte lipid accumulation in these hearts very likely reflects myocardium ventricular contractile dysfunction. In addition, the increased expression of iNOS and the evidence for the significant presence of peroxynitrite in cardiomyocytes and interstitial macrophage cell types suggest that oxidative damage may play a role in actin/myosin disruption in the hearts of septic patients.     

Elevated nucleosome levels in systemic inflammation and sepsis

OBJECTIVE: Multiple organ dysfunction syndrome is a frequent complication of severe sepsis and septic shock and has a high mortality. We hypothesized that extensive apoptosis of cells might constitute the cellular basis for this complication. DESIGN: Retrospective study. SETTING: Medical and surgical wards or intensive care units of two university hospitals. PATIENTS: Fourteen patients with fever, 15 with systemic inflammatory response syndrome, 32 with severe sepsis, and eight with septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We assessed circulating levels of nucleosomes, specific markers released by cells during the later stages of apoptosis, with a previously described enzyme-linked immunosorbent assay in these 69 patients with fever, systemic inflammatory response syndrome, severe sepsis, or septic shock. Severity of multiple organ dysfunction syndrome was assessed with sepsis scores, and clinical and laboratory variables. Elevated nucleosome levels were found in 64%, 60%, 94%, and 100% of patients with fever, systemic inflammatory response syndrome, severe sepsis, or septic shock, respectively. These levels were significantly higher in patients with septic shock as compared with patients with severe sepsis, systemic inflammatory response syndrome, or fever, and in nonsurvivors as compared with survivors. In patients with advanced multiple organ dysfunction syndrome, nucleosome levels correlated with cytokine plasma levels as well as with variables predictive for outcome. CONCLUSIONS: Patients with severe sepsis and septic shock have elevated plasma levels of nucleosomes. We suggest that apoptosis, probably resulting from exposure of cells to excessive amounts of inflammatory mediators, might by involved in the pathogenesis of multiple organ dysfunction syndrome.     

Myocardial dysfunction in meningococcal septic shock

PURPOSE OF REVIEW: The underlying pathophysiology of sepsis has long been disputed. Systemic vasodilatation is important in the development of shock and, in septic critically ill adults who have been volume resuscitated, the systemic pressure is often low and the cardiac output high. In septic children however, and especially in those with meningococcal septic shock, poor cardiac output as a consequence of depressed myocardial function seems to be important, often being the cause of death in these patients. There is much evidence for disturbance of myocardial performance, yet despite the literature, there is still no consensus on how best to manage this complication of meningococcal disease. RECENT FINDINGS: Many mediators have been proposed as the cause of the reduced myocardial performance, most recently interleukin-6 has emerged as a possible candidate involved in the pathophysiology of the myocardial dysfunction. Cardiac troponin I has been shown to be a marker of myocardial injury and may be used to monitor left ventricular function. Newer treatments emerging to manage the dysfunction include reports of success with phosphodiesterase inhibitors. SUMMARY: Accepting that myocardial dysfunction may be an important cause of the shock state in overwhelming meningococcal disease, the approach to management may need to be tailored appropriately. Although presently there is no targeted treatment, it may be that therapy focused on inhibiting or antagonising interleukin-6 will be helpful in the future. Regardless of the importance of myocardial depression, fluid resuscitation remains a cornerstone in the management of severe meningococcal disease.     

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.     

Characterization of a myocardial depressant factor in meningococcal septicemia

OBJECTIVE: Identification and characterization of myocardial depressant factors present in meningococcal septicemia. DESIGN: Laboratory investigation of myocardial depression that used isolated cardiac myocytes as an model of cardiac contractile function. SETTING: University hospital and laboratories. PATIENTS: Children with severe meningococcal septic shock requiring intensive care. ANIMALS: Myocytes obtained from adult male Sprague-Dawley rats. INTERVENTIONS: Serum samples obtained from the acute phase of sepsis were evaluated for the presence of myocardial depressant activity. Further characterization of the myocardial depressant factor was undertaken by using cell culture supernatants from whole blood and peripheral blood mononuclear cells that had been exposed to heat-killed meningococci. MEASUREMENTS AND MAIN RESULTS: Myocardial depressant activity was measured by using isolated rat left-ventricular myocytes. Changes in amplitude of contraction and in the speed of contraction and relaxation were determined after cells were exposed to various stimuli. Serum from patients with meningococcal disease had myocardial depressant activity. This activity was also present in whole blood and peripheral blood mononuclear cells exposed to meningococci. Myocardial depressant activity was found to be heat stable, proteinaceous, and of a molecular weight range of 10-25 kDa. The activity did not elevate concentrations of cyclic guanylic acid. Lipopolysaccharide-binding protein augmented the release of myocardial depressant factor by peripheral blood mononuclear cells exposed to meningococci. CONCLUSIONS: Myocardial depression in meningococcal sepsis is mediated in part by circulating myocardial depressant factors. Myocardial depressant factors are also released when whole blood or peripheral blood mononuclear cells of healthy donors are exposed to heat-killed meningococci. Release of the factors appears to be mediated through endotoxin-induced activation of peripheral blood mononuclear cells, since lipopolysaccharide-binding protein augments release in a dose-responsive manner. Partial physicochemical characterization of the factors has been achieved.     

Dysfonction myocardique et sepsis : physiopathologie et perspectives thérapeutiques

In the 40% of patients with sepsis who develop cardiovascular disturbances, mortality increases from 20 to 70–80%. These rates have changed little in recent years despite significant advances in the field of antimicrobial and intensive care therapies. Peripheral circulatory abnormalities usually observed in septic shock lead to difficulties in the demonstration of autonomous cardiac involvement, i.e., independent of loading conditions. Although exact mechanisms leading to myocardial dysfunction in sepsis are multiple and may involve several inflammatory mediators, the reality of this septic myocardial dysfunction is now firmly established on the basis of animal and clinical studies. Nitric oxide seems to play a pivotal role at the cellular level, being implicated in the transmission of different cytosolic signals leading to impaired contractile abnormalities. A better knowledge of the pathophysiology of this syndrome will improve the treatment modalities of septic cardiac dysfunction.     

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.     

Bench-to-bedside review: Sepsis - from the redox point of view

The pathogenesis of sepsis and its progression to multiple organ dysfunction syndrome and septic shock have been the subject of investigations for nearly half a century. Controversies still exist with regard to understanding the molecular pathophysiology of sepsis in relation to the complex roles played by reactive oxygen species, nitric oxide, complements and cytokines. In the present review we categorise the key turning points in sepsis development and outline the most probable sequence of events leading to cellular dysfunction and organ failure under septic conditions. We have applied an integrative approach in order to fuse current state-of-the-art knowledge about redox processes involving hydrogen peroxide, nitric oxide, superoxide, peroxynitrite and hydroxyl radical, which lead to mitochondrial respiratory dysfunction. Finally, from this point of view, the potential of redox therapy targeting sepsis is discussed.     

Sepsis sévère et grossesse

Severe sepsis or septic shock during pregnancy or in the post partum period are rare. Only twelve percent of maternal mortality is due to severe sepsis or septic shock. The immune status and the modifications of the cardiovascular system during pregnancy explain the relatively good tolerance of women with bacteremia or an infection. On the other hand, myocardial dysfunction, which may develop rapidly, is associated with a poor prognosis. Sepsis syndrome must be recognized soon in order to start an empirical and effective antibiotherapy based on microbiological data related to the source of the infection. Maternal and foetal tolerance to antibiotics must be considered, as well as the dose regimen in accordance with the increase of volumes of distribution. Conventional therapy for sepsis or septic shock must conform to the current guidelines.     

Significance and interpretation of elevated troponin in septic patients

Because no bedside method is currently available to evaluate myocardial contractility independent of loading conditions, a biological marker that could detect myocardial dysfunction in the early stage of severe sepsis would be a helpful tool in the management of septic patients. Clinical and experimental studies have reported that plasma cardiac troponin levels are increased in sepsis and could indicate myocardial dysfunction and poor outcome. The high prevalence of elevated levels of cardiac troponins in sepsis raises the question of what mechanism results in their release into the circulation. Apart from focal ischemia, several factors may contribute to the microinjury and minimal myocardial cell damage in the setting of septic shock. A possible direct cardiac myocytotoxic effect of endotoxins, cytokines or reactive oxygen radicals induced by the infectious process and produced by activated neutrophils, macrophages and endothelial cells has been postulated. The presence of microvascular failure and regional wall motion abnormalities, which are frequently observed in positive-troponin patients, also suggest ventricular wall strain and cardiac cell necrosis. Altogether, the available studies support the contention that cardiac troponin release is a valuable marker of myocardial injury in patients with septic shock.     

Bench-to-bedside review: Significance and interpretation of elevated troponin in septic patients

Because no bedside method is currently available to evaluate myocardial contractility independent of loading conditions, a biological marker that could detect myocardial dysfunction in the early stage of severe sepsis would be a helpful tool in the management of septic patients. Clinical and experimental studies have reported that plasma cardiac troponin levels are increased in sepsis and could indicate myocardial dysfunction and poor outcome. The high prevalence of elevated levels of cardiac troponins in sepsis raises the question of what mechanism results in their release into the circulation. Apart from focal ischemia, several factors may contribute to the microinjury and minimal myocardial cell damage in the setting of septic shock. A possible direct cardiac myocytotoxic effect of endotoxins, cytokines or reactive oxygen radicals induced by the infectious process and produced by activated neutrophils, macrophages and endothelial cells has been postulated. The presence of microvascular failure and regional wall motion abnormalities, which are frequently observed in positive-troponin patients, also suggest ventricular wall strain and cardiac cell necrosis. Altogether, the available studies support the contention that cardiac troponin release is a valuable marker of myocardial injury in patients with septic shock.     

Sodium/hydrogen exchange activity in sepsis and in sepsis complicated by previous injury: 31P and 23Na NMR study

OBJECTIVE: Sepsis or septic shock occurs frequently in sick and injured patients and is associated with a significant mortality. Myocardial contractile dysfunction has been proposed to be a major determinant of sepsis-related mortality. This study was directed to examine the role of Na/H exchange activity in myocardial defects after sepsis or after sepsis complicated by a previous burn injury. DESIGN: Laboratory study. SETTING: University research laboratory. SUBJECTS: Sprague-Dawley rats (300-350 g, males). INTERVENTIONS: Cardiac function, cellular Na and Ca, myocardial pH, and high-energy phosphates were examined in perfused hearts harvested after sepsis alone (intratracheal Streptococcus pneumoniae, 0.4 mL of 1 x 10 CFU/mL), after sepsis complicated by previous burn injury (40% total body surface area), and after amiloride (a selective inhibitor of Na/H exchange) treatment of either sepsis alone or sepsis plus burn. MEASUREMENTS AND RESULTS: The ratio of Na signal from the intracellular compartment (Nai) compared with an external standard (monitored by Na-NMR spectroscopy, TmDOTP shift reagent) increased by 70% in sepsis alone and by 41% in sepsis complicated by previous burn injury compared with shams. Cardiac adenosine triphosphate and intracellular pH (P nuclear magnetic resonance spectroscopy) were unchanged by sepsis or sepsis plus burn. Left ventricular pressure and maximal change in pressure over time were reduced after sepsis or after sepsis plus burn injury. Amiloride treatment in either sepsis or sepsis complicated by a previous burn injury prevented myocardial Na and Ca accumulation, attenuated sepsis-related lactic acidosis, and improved left ventricular function. CONCLUSION: Our results suggest that sepsis-related cardiac dysfunction is mediated, in part, by Na/H exchange activity, and inhibition of Na/H exchange activity improves cardiac function after sepsis alone or sepsis complicated by a previous injury.     

Clinical utility of B-type natriuretic peptide in early severe sepsis and septic shock

B-type natriuretic peptide (BNP) has diagnostic, therapeutic, and prognostic utility in critically ill patients. For severe sepsis and septic shock patients in particular, similar clinical utility from the most proximal aspects of hospital presentation to the intensive care unit has not been examined. BNP levels were measured at 0, 3, 6, 12, 24, 36, 48, 60, and 72 hours in 252 patients presenting to the emergency department with severe sepsis and septic shock. The clinicians were blinded to the BNP levels. Elevated BNP levels (>100 pg/mL) were seen in 42% and 69% of patients on presentation and at 24 hours, respectively. Elevated BNP ranges (>230 pg/mL) were significantly associated with myocardial dysfunction and severity of global tissue hypoxia. When adjusted for age, gender, history of heart failure, renal function, organ dysfunction, and mean arterial pressure, a BNP greater than 210 pg/mL at 24 hours was the most significant independent indicator of increased mortality: odds ratio 1.061 (1.026-1.097), P < .001, 95% confidence interval. Patients with severe sepsis and septic shock often have elevated BNP levels, which are significantly associated with organ and myocardial dysfunction, global tissue hypoxia, and mortality. Serial BNP levels may be a useful adjunct in the early detection, stratification, treatment, and prognostication of high-risk patients.