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500 CI = cardiac index; cNOS = constitutive nitric oxide synthase; CO = cardiac output; CVP = central venous pressure; IL = interleukin; iNOS = inducible nitric oxide synthase; LVEDVI = left ventricular end-diastolic volume index; LVEF = left ventricular ejection fraction; MDS = myocardial depressant substance; NO = nitric oxide; PAC = pulmonary artery catheter; PAWP = pulmonary artery wedge pressure; RVEF = right ventricular ejection fraction; SVR = systemic vascular resistance; TNF-α = tumor necrosis factor alpha. Critical Care December 2002 Vol 6 No 6 Court et al. Sepsis and septic shock have been recognized as an increasingly serious clinical problem, accounting for substan- tial morbidity and mortality. The past four decades have seen the age-adjusted mortality of sepsis increase from 0.5 to 7 per 100,000 episodes despite major advances in the under- standing of its pathophysiology [1]. The incidence of severe sepsis in the United States today is estimated at 750,000 cases per year, resulting in 215,000 deaths annually [2]. The majority of these sepsis patients die of refractory hypotension and of cardiovascular collapse. Sepsis has been defined as the systemic inflammatory response to infection [3]. An infectious stimulus (e.g. endo- toxin or another microbiologic element) induces the release of local and systemic inflammatory mediators, especially tumor necrosis factor alpha (TNF-α) and IL-1β, from monocytes/ macrophages and other cells [4]. These cytokines stimulate polymorphonuclear leukocytes, macrophages and endothelial cells to release a number of downstream inflammatory media- tors, including platelet activating factor and nitric oxide (NO), further amplifying the inflammatory response. Several anti- inflammatory mediators are also released as part of this ampli- fication cascade; namely, IL-10, transforming growth factor beta and IL-1 receptor antagonist. The relative contribution of these cytokines will determine the severity of the septic episode. If the inflammatory reaction is particularly intense, homeostasis of the cardiovascular system will be disrupted, leading to septic shock. One of the manifestations of cardio- vascular dysfunction in septic shock is myocardial depression. The present article reviews the clinical manifestations of cardiac dysfunction in sepsis, from the point of view of both the right and left ventricle, as well as cardiovascular prognos- tic factors in sepsis and septic shock. We will also review the Review Clinical review: Myocardial depression in sepsis and septic shock Olivier Court1, Aseem Kumar2, Joseph E Parrillo3 and Anand Kumar4 1Fellow, Section of Critical Care Medicine, Health Sciences Center, University of Manitoba, Winnipeg, Canada 2Assistant Professor of Medicine, Section of Critical Care Medicine, Rush–Presbyterian–St Luke’s Medical Center, Chicago, IL, USA 3Director, Division of Cardiovascular Diseases and CCM, Cooper Hospital, Camden, NJ, USA 4Assistant Professor of Medicine, Section of Critical Care Medicine, Health Sciences Center, University of Manitoba, Winnipeg, Canada Correspondence: Anand Kumar, akumar61@yahoo.com Published online: 12 September 2002 Critical Care 2002, 6:500-508 (DOI 10.1186/cc1822) This article is online at http://ccforum.com/content/6/6/500 © 2002 BioMed Central Ltd (Print ISSN 1364-8535; Online ISSN 1466-609X) Abstract 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-1β. 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. Keywords contractility, cytokine, heart, myocardial depression, nitric oxide 501 Available online http://ccforum.com/content/6/6/500 potential pathophysiologic processes responsible for myocar- dial depression in sepsis, from the perspective of organ phys- iology and molecular biology. Clinical manifestations of cardiovascular dysfunction Historical perspectives Our understanding of the cardiovascular manifestations of septic shock has evolved over the years, as new techniques to assess cardiovascular performance have become avail- able. Before the introduction of the pulmonary artery catheter (PAC), two distinct cardiovascular clinical presentations of septic shock were described: a high cardiac output (CO) state, associated with warm, dry skin and a bounding pulse despite hypotension (warm shock); and a low CO state, associated with hypotension, cold, clammy skin and a thready pulse (cold shock) [5]. Clowes et al. [6], in a 1966 study, described these two clinical pictures as different stages of septic shock: patients were believed to initially experience a hyperdynamic phase (warm shock), and then to either recover or progress to hypodynamic shock (cold shock) and death. This view was reinforced by other clinical studies [5,7] that correlated survival with high cardiac index (CI). Only a few studies hinted at the relationship between volume status, the CI and outcome [8,9]. All these studies that supported the concept of terminal cold shock suffered from the fact that they used central venous pressure (CVP) as the best avail- able estimate of left ventricular end-diastolic volume and ade- quacy of resuscitation. Evidence accumulated over the past 40 years shows that CVP, as a reflection of right ventricular preload, is a poor estimate of left ventricular preload in criti- cally ill patients, and particularly in sepsis [10]. The introduction of the PAC (which could measure pulmonary artery wedge pressure as a more accurate estimate of left ventricular preload) has allowed for better definition of the cardiovascular dysfunction in septic shock and has improved volume resuscitation. Several studies have shown that ade- quately resuscitated septic shock patients consistently mani- fest a hyperdynamic circulatory state with high CO and low systemic vascular resistance (SVR) [11,12]. In contrast to previous belief, this hyperdynamic state usually persists until death in nonsurvivors (Fig. 1) [13,14]. Despite the strong evi- dence characterizing sepsis as a hyperdynamic state, studies that examined myocardial performance still showed left ven- tricular dysfunction (illustrated by decreased left ventricular stroke work index) in properly resuscitated septic patients [15]. The depression in the Frank–Starling curve demon- strated in these studies, however, could be explained by either a change in myocardial contractility or compliance. The development of portable radionuclide cineangiography and its application to critically ill patients has further improved our understanding of cardiovascular dysfunction in septic shock, by allowing differentiation between impaired contractil- ity and impaired compliance. Left ventricular function Parker et al. [16] showed, using radionuclide cineangiogra- phy, that survivors of septic shock demonstrated a decreased left ventricular ejection fraction (LVEF) and an acutely dilated left ventricle, as evidenced by an increased left ventricular end-diastolic volume index (LVEDVI) (Fig. 2). These parame- ters returned to normal over 7–10 days in survivors. Nonsur- vivors maintained normal LVEF and LVEDVI throughout the course of their illness until death. All patients in this study [16] had normal or elevated CI and low SVR, as measured by the PAC. In 1988, Ognibene et al. compared left ventricular perfor- mance curves (plotting left ventricular stroke work index versus LVEDVI) of septic and nonseptic critically ill patients (Fig. 3). They showed a flattening of the curve in septic shock patients, with significantly smaller left ventricular stroke work index increments in response to similar LVEDVI increments when compared with nonseptic critically ill controls [17]. Subsequent studies have confirmed the presence of signifi- cant left ventricular systolic dysfunction in septic patients [18,19]. Figure 1 The mean (± SEM) cardiac index plotted against time for all patients, survivors, and nonsurvivors. The hatched areas show the normal range. All groups maintained an elevated cardiac index throughout the study period. The difference between the survivors and nonsurvivors was not statistically significant. Reproduced with permission from [16]. 502 Critical Care December 2002 Vol 6 No 6 Court et al. Left ventricular diastolic function in septic shock is not as clearly defined. The dilatation of the left ventricle [16] and the lack of discordance between pulmonary artery wedge pres- sure (PAWP) and left ventricular end-diastolic volume [17] both argue against significant diastolic dysfunction in sepsis. More recent studies using echocardiography, however, have demonstrated slower left ventricular filling [20] and aberrant left ventricular relaxation [21,22] in septic patients, suggest- ing that impaired compliance may significantly contribute to myocardial depression in sepsis. Right ventricular function Low peripheral vascular resistance in sepsis leads to decreased left ventricular afterload. However, the right ven- tricular afterload is frequently elevated due to increased pul- monary vascular resistance from acute lung injury [23]. These different physiologic conditions mean that the right ventricle cannot be expected to behave like the left ventricle in septic patients. Multiple studies have therefore specifically examined right ventricular function in sepsis. A number of studies have documented right ventricular sys- tolic dysfunction in volume-resuscitated septic patients, as evidenced by decreased right ventricular ejection fraction (RVEF) and right ventricular dilation [24–27]. Kimchi et al. [24] and Parker et al. [26] also showed that right ventricular dysfunction occurred independently of pulmonary vascular resistance and pulmonary artery pressure, suggesting that increased right ventricular afterload could not be the domi- nant cause of right ventricular depression in septic shock. Parker et al. [26] further demonstrated a close temporal par- allel between right ventricular and left ventricular dysfunction in sepsis. In their study, survivors experienced significant right ventricular dilation and decreased RVEF and right ventricular stroke work index, all of which returned to normal within 7–14 days (Fig. 4). Nonsurvivors had moderate right ventricu- lar dilation and a marginally decreased RVEF, neither of which improved throughout their illness. There is also evidence of right ventricular diastolic dysfunc- tion in septic patients. Kimchi et al. [24] noticed a lack of cor- relation between right atrial pressure and right ventricular Figure 2 The mean (± SEM) left ventricular ejection fraction (LVEF) plotted versus time for all patients, survivors, and nonsurvivors. Overall, septic shock patients showed a decreased LVEF at the time of initial assessment. This effect was due to marked early depression of LVEF among survivors that persisted for up to 4 days and returned to normal within 7–10 days. Nonsurvivors maintained LVEF in the normal range. The hatched area represents the normal range. Reproduced with permission from [16]. Figure 3 Frank–Starling ventricular performance relationship for each of the three patient groups. Data points plotted represent the mean prevolume and postvolume infusion values of end-diastolic volume index (EDVI) and left ventricular stroke work index (LVSWI) for each patient group. Control patients showed a normal increase of EDVI and LVSWI in response to volume infusion. The absolute increases of EDVI and LVSWI in patients with sepsis without shock were less than those of control subjects, but the slope of the curve is similar to control patients. Patients with septic shock had a greatly diminished response and showed a marked rightward and downward shift of the Frank–Starling relationship. Reproduced with permission from [17]. 503 end-diastolic volume, suggesting altered right ventricular compliance. Schneider et al. [25] similarly identified a sub- group of patients who failed to exhibit an increased right ven- tricular end-diastolic volume index in response to volume loading, despite a rise in CVP. However, the relative contribu- tion of systolic and diastolic dysfunction to right ventricular depression in sepsis remains largely unknown. Cardiovascular prognostic factors in septic shock Early studies of cardiovascular dysfunction in septic shock suggested that a low or decreasing CI invariably carried a poor prognosis [5–8]. As previously discussed, these studies relied on CVP measurements to assess volume status. It is now known that CVP is a poor reflection of left ventricular preload in critical illness and cannot accurately determine adequacy of resuscitation. Introduction of the PAC showed that adequately volume-resuscitated septic shock patients (as measured by PAWP) predictably exhibited a high CI and low SVR, including nonsurvivors [11,12]. CI is therefore not a reli- able predictor of mortality in sepsis. Recognition of the significant post-resuscitation peripheral vasodilation (low SVR) in septic shock led to the theory that peripheral vascular failure could be a major determinant of mortality in septic shock. Baumgartner et al. [28] noticed that patients with an extremely high CI (> 7.0 l/min/m2) and low SVR had a uniformly poor outcome. Groeneveld et al. [29] retrospectively examined data from septic shock patients. They found that, for equivalent CI, nonsurvivors had a lower SVR than survivors. They concluded that peripheral vascular resistance was closely linked to outcome in septic shock. Parker et al. [13] reviewed hemodynamic data from septic shock patients on presentation and at 24 hours to identify prognostic value. They found that, on presentation, only a heart rate <106 beats/min suggested a favorable outcome. At 24 hours, a heart rate <95 beats/min, a SVR index >1529 dynes s cm5/m2, a decrease in heart rate >18 beats/min and a decrease in CI > 0.5 l/min/m2 all pre- dicted survival. In a subsequent study [14], the same authors confirmed previous findings of decreased LVEF and increased LVEDVI in survivors of septic shock but not in non- survivors. However, although nonsurvivors as a whole did not exhibit left ventricular dilation, they could be divided into two groups: the first with decreasing LVEDVI and decreasing CI on serial measurements, and the other group with progres- sively increasing LVEDVI and maintained CI. There are three hemodynamic patterns of death in septic shock [13]. Early deaths are due either to distributive shock (low SVR and refractory hypotension despite preserved CI) or to a cardiogenic form of septic shock (decreased CI). Late deaths are due to multisystem organ failure. Correlating this with Parker et al.’s [14] findings, it is possible that nonsur- vivors who are unable to dilate their left ventricle (decreasing LVEDVI and CI) succumb to the cardiogenic form of septic shock. Those who have increasing LVEDVI and preserved CI die of the classic distributive shock. The value of right ventricular performance parameters in pre- dicting outcome is less clear. Multiple studies [24–27] have shown that, in sepsis, the right ventricle behaves similar to the left ventricle, exhibiting acute dilation and decreased RVEF. Persistence of right ventricular systolic dysfunction is associated with poor outcome [26,27]. Opinions diverge, however, on whether initial right ventricular dilation and decreased RVEF portend poor prognosis. Vincent et al. [27] suggested that survival correlates with higher initial RVEF, whereas Parker et al. [26] observed lower RVEF in survivors of septic shock than in nonsurvivors. The question requires further study. Patients with sepsis and septic shock can show resistance to the vasopressor and inotropic effects of catecholamines. Nonsurvivors of septic shock have been shown to have an attenuated inotropic response to a dobutamine stress test compared with survivors [30]. Conversely, increased SVI, increased mixed venous oxygen saturation, ventricular dilation and drop in diastolic blood pressure in response to a dobuta- mine stress test all predict survival in septic patients [31]. Etiology of myocardial depression in sepsis and septic shock Myocardial hypoperfusion The possibility of myocardial dysfunction in sepsis was origi- nally proposed and described in the 1960s. Its etiology, however, remained a mystery. For many years, the leading theory was that sepsis was associated with a globally Available online http://ccforum.com/content/6/6/500 Figure 4 Serial changes in right ventricular ejection fraction and end-diastolic volume index during septic shock in humans. (a) Mean initial and final right ventricular ejection fractions for survivors (closed circles, P < 0.001) and nonsurvivors (open circles, P < 0.001). (b) Mean initial and final right ventricular end-diastolic volume index for survivors (closed circles, P < 0.05) and nonsurvivors (open circles, P = not significant). The right ventricle, similar to the left ventricle, undergoes dilation with a drop in ejection fraction with the acute onset of septic shock. In 7–10 days, right ventricular dilation and decreased ejection fraction revert to normal in survivors. Data from [26]; adapted with permission [69]. 504 decreased myocardial perfusion, leading to ischemic injury and myocardial depression. Two studies disproved that view. Cunnion et al. [32] performed serial measurements of coro- nary blood flow and metabolism using thermodilution coro- nary sinus catheters in septic patients (Fig. 5). They found normal or elevated coronary blood flow in septic patients compared with normal controls with comparable heart rates, and found no difference in blood flow between patients who developed myocardial dysfunction and those who did not. There was no net myocardial lactate production. Dhainaut et al. [33], using the same technique, confirmed these findings. Furthermore, studies on animal models of sepsis [34] demon- strated that myocardial oxygen metabolism and high-energy phosphates were preserved in septic shock, neither of which is compatible with myocardial ischemia. However, Turner et al. [35] recently measured increased troponin I levels in patients with septic shock, demonstrating some degree of myocardial cell injury in the course of septic shock. It remains unclear from their study whether direct cardiac injury plays a role in sepsis-induced myocardial dysfunction or is the result of other factors, including a myocardial depressant substance (MDS) or exogenous catecholamine administration. Circulatory depressant substances Wiggers’ landmark report [36] in 1947 postulating the pres- ence of a circulating myocardial depressant factor in hemor- rhagic shock provided the basis for the accepted current theory of myocardial dysfunction in septic shock. The pres- ence of a myocardial depressant factor in sepsis was later confirmed experimentally by Lefer [37] in the late 60s. Clinical studies performed at the same time associated death from septic shock with a hypodynamic circulatory state marked by a decreased CO [6–8]. Although these earlier studies depended on the measurement of CVP to assess preload, a factor now recognized as