Cardiac dysfunction in sepsis: new theories and clinical implications
Received: 6 August 1997 Accepted: 16 September 1997
R. M. Grocott-Mason. A. M. Shah ( ~ ) Department of Cardiology, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, UK
Introduction
The syndrome of septic shock is characterised by hypo- tension and multiple organ failure resulting from sys- temic release of inflammatory cytokines in response to an infective organism [1]. A similar clinical picture may be seen in other conditions in which systemic cytokines are released, such as severe burns and acute pancreati- tis. The term "systemic inflammatory response syn- drome" has been used for these conditions, which are thought to share common pathophysiological mecha- nisms [2]. Intrinsic cardiac dysfunction is a well docu- mented feature of septic shock syndrome [3, 4]. In this article we review the pattern of cardiac impairment de- scribed in septic shock, experimental and clinical studies relating to the pathophysiological mechanisms involved, and therapeutic strategies. Although clearly important in the clinical setting, we do not discuss the interaction of sepsis with pre-existing cardiac disease (e. g. ischae- mic heart disease) or primary cardiac infection (i. e. in- fective endocarditis).
What changes in cardiac function occur?
Systolic depression
The haemodynamic profile characteristic of septic shock is hypotension with profound systemic vasodilatation, yet in conjunction with a normal or even supranormal cardiac output. Assessment of intrinsic myocardial func- tion is complicated by marked alterations in haemody- namic load and heart rate, which are frequently ob- served in sepsis. Initial muscle length is a major determi- nant of the force of cardiac muscle contraction (the Frank-Starling mechanism), as is the frequency of con- traction and the force against which the muscle has to contract (afterload) (Fig. 1). In septic shock both tachy- cardia and a reduction in afterload contribute to an in- crease in cardiac output. On the other hand, hypovolae- mia reduces preload and thus left ventricular end-dia- stolic volume, which leads to a decrease in cardiac out- put by reducing muscle stretch (Fig.2). Nevertheless, clinical and experimental studies that have attempted to assess cardiac function independent of changes in load or heart rate indicate the presence of true, intrinsic myocardial depression. Thus, although stroke volume index (stroke volume normalised for body surface area) is often normal, left ventricular ejection fraction (LVEF) is usually depressed. The stroke work index (SWI; stroke volume x mean arterial blood pressure, normalised for body surface area) "corrects" for the re- duced afterload and is also depressed. The preload- SWI relation, an estimate of the Frank-Starling relation, is shifted down and to the right in these patients [5]. Similar data have been reported in animal models of septic shock, and it has been shown that the end-systolic pressure-volume relationship (probably the best "load- independent" measure of "contractility") is depressed [6]. Typically, cardiac dysfunction is detectable within the first 24 h of the development of septic shock and is completely reversible in survivors (by 7 to 10 days) [3,
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sv rl°ad
J ~ Increased afterload
PCWP
SV
B
PCWP
LVSWI Increased contractility
/ X Normal
~ Reduced contractility
PCWP Fig.1 Graphs illustrating the interrelationship among muscle length (determined by preload), afterload and contractility. In both panels, pulmonary capillary wedge pressure PCWP is the in- direct measurement of "preload", which determines initial muscle length. A rise in preload increases cardiac performance (the Frank-Starling response), measured as LV stroke volume SV top panel or LV stroke work index LVSWI bottom panel. The top pa- nel shows that SV is inversely related to afterload, whereas the use of LVSWI bottom panel "corrects" for changes in afterload (since LVSWI = LVSVI × mean blood pressure). The effects of changes in myocardial "contractility" are shown in the bottom pa- nel
4, 7]. Similar changes have also been reported in right ventricular function [8].
Left ventricular dilatation
Patients with septic shock also develop dilatation of the LV without corresponding increases in LV end-diastolic pressure, suggesting an increase in LV compliance. Of- ten, these changes may only be apparent after a fluid challenge. Detailed serial studies of patients (and ani- mals) with septic shock have shown that the occurrence of LV dilatation is associated with better prognosis and lower mortality. This has led to the hypothesis that the observed LV dilatation is a compensatory response to myocardial depression, allowing the LV to maintain car- diac output through utilisation of its preload reserve (i. e. the Frank-Starling mechanism) [6, 7]. Indeed, the failure of LV dilatation appears to be detrimental [7].
SV
...-'' C "A" .....
PCWP Fig,2 These figures illustrate the interaction between the typical changes in ventricular loading and myocardial contractility ob- served in septic shock on the SV-PCWP relationship. In both pa- nels, point A is the normal starting position. Reduction in afterload induces the change to point B; B to C is the result of the reduction in preload; C to D is a downward shift due to a reduction in myo- cardial contractility; the hatched line from D to E is the expected response to an increase in preload (PCWP) with volume loading. In the top panel there is only a small negative inotropic effect, whereas the bottom panel illustrates the effect of a larger myocar- dial depressant effect. In the scenario of the top panel the reduc- tion in myocardial contractility may not be clinically apparent since SV is not decreased, whereas it is more likely to be detected in the bottom panel. However, the LVSWI at a given filling pres- sure will be reduced in both cases
Assessment of cardiac function in patients
In clinical practice, a simple and relatively load-inde- pendent assessment of ventricular function may be made by the pulmonary capillary wedge pressure (PCWP)-LVSWI relationship, assessed during volume expansion (i. e. over a range of PCWP). Depressed sys- tolic function is indicated by a shift in this relationship to the right and downwards (Fig. 1). Two-dimensional echocardiography (either transthoracic or transoeso- phageal) is also a valuable investigation, the hallmarks of sepsis-induced cardiac dysfunction being increased LV end-diastolic volume and reduced LVEF due to global hypokinesis. Although several echocardiograph- ic/Doppler parameters suggestive of diastolic dysfunc- tion have been described, their interpretation (and thus their clinical usefulness) is hampered by the critical de- pendence of these measurements on filling pressures and chamber compliance [9]. Cardiac output or cardiac index give a very poor assessment of intrinsic cardiac
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function in view of the associated changes in load (espe- cially afterload) and heart rate.
Aetiological mechanisms
Several hypotheses have been proposed to explain the cardiac dysfunction of septic shock, including myocar- dial ischaemia and hypoperfusion (leading to a deficit in high energy phosphates), microvascular dysfunction, the presence of activated leucocytes and the effects of various circulating and/or locally produced mediators on the heart.
Role of myocardial ischaemia and microvascular dysfunction
Global myocardial ischaemia has been excluded as an important pathophysiological mechanism by a number of clinical studies showing that total coronary blood flow is not reduced [10] and that myocardial lactate pro- duction is not elevated in patients with septic shock [11]. Experimental studies (e. g. with nuclear magnetic reso- nance spectroscopy) have shown no impairment of high energy phosphate metabolism [12]. However, regional myocardial ischaemia or infarction may be complica- tions in patients with coexistent (possibly previously un- known) coronary artery disease, a factor which should be borne in mind particularly in patients with identifi- able risk factors. Generalised microvascular dysfunction is a prominent feature of septic shock and is probably an important factor in the heart as elsewhere [13]. This could lead to relative ischaemia, or flow heterogeneity secondary to mechanisms such as leucocyte plugging of capillaries, interstitial oedema and free radical produc- tion [14]. Endothelial dysfunction may also affect myo- cardial function secondary to altered release of cardio- active substances [15] (see below).
Table 1 List of factors which may contribute to the cardiac dys- function seen in septic shock. See text for cellular sources of these agents and detailed discussion
Potential mediators of myocardial depression in sepsis
Bacterial components, e.g. endotoxin Cytokines, e.g. tumour necrosis factor-alpha (TNFc0, interleukins (IL-1, IL-2, IL-6) Platelet activating factor Arachidonic acid derivatives, e.g. leukotrienes, prostaglandin Kinins, e.g. bradykinin, vasoactive intestinal peptide Complement components, e.g. C5a Endothelial factors, e. g. nitric oxide, endothelin Reactive oxygen species, e.g. superoxide, peroxynitrite, hydroxyl ions Other myocardial depressant factors
lary muscles [17, 18]. Furthermore, in clinical studies, the presence of such activity was associated with greater cardiac dysfunction, manifest as increased LV diastolic volume indices, higher PCWP, lower LVEE higher se- rum lactate levels and a trend towards increased mortal- ity [18]. Although these early studies suggested the pre- sence of a single substance, it now seems more likely that the myocardial depression involves multiple fac- tors. No novel MDS has yet been positively identified, and recently "MDS" activity in the serum of patients with acute septic shock was attributed to a synergistic effect of the cytokines, tumour necrosis factor-alpha (TNFc 0 and interleukin 1/3 (IL-1/3) [19]. Consequently, attention has focused increasingly on the role of the dif- ferent inflammatory cytokines and other substances known to be released in septic shock (Table 1), and on bacterial products such as endotoxin from gram-nega- tive bacteria and other bacterial cell membrane compo- nents which appear to be the initial triggers for the de- velopment of septic shock syndrome.
Myocardial depressant substances
The main mechanism of myocardial dysfunction ap- pears to be due to the direct effects of various circulat- ing and local mediators, produced by several cell types including bacteria, white blood cells and endothelial cells (Table 1). Lefer and Rovetto [16] originally postu- lated the existence of a circulating myocardial depres- sant substance(s) (MDS) in septic shock in 1970. Several groups subsequently supported this hypothesis in studies performed in different species, including hu- mans; for instance, serum from patients/animals with septic shock was shown to have negative inotropic activ- ity on isolated myocardial preparations, including cul- tured neonatal rat cardiac myocytes and isolated papil-
Endotoxin (and other bacterial components)
Bacterial endotoxins are lipopolysaccharide molecules contained in the cell membrane of gram-negative bac- teria and released during infection with such organisms. Following intravenous infusion of endotoxin into healthy human volunteers, the typical haemodynamic profile of septic shock (tachycardia, reduced systemic vascular resistance, increased cardiac index) develops over 3 to 5 h [20]. LV diastolic compliance (assessed by end-diastolic pressure-volume ratio) is increased and systolic function (assessed by LVEF) decreased. The time course of onset of these effects suggests that they are not direct effects of endotoxin itself, and indeed the cardiovascular effects are preceded by a transient rise
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in the levels of cytokines such as TNFa [20]. In a clinical observational study, endotoxin was detected in the se- rum of 43 % of patients with septic shock and associated with more cardiac dysfunction and higher mortality [21]. However, septic shock and cardiac dysfunction can oc- cur in the absence of endotoxaemia, consistent with the idea that endotoxin only triggers a cascade of events leading to cardiac dysfunction and does not itself cause myocardial depression. Recent studies suggest that "ac- tivated" leucocytes play an important role in this cas- cade. Granton and colleagues [22] used blood from an endotoxin-treated rabbit to perfuse simultaneously two isolated rabbit hearts. Removal of leucocytes from the blood perfusing one of the hearts prevented the de- crease in LV contractility and morphological changes otherwise observed, suggesting that the activated white blood cells were necessary for induction of myocardial dysfunction in this model [22]. The cytokine-mediated effects of endotoxin are further discussed below. Bacter- ial components other than endotoxin can also trigger a similar cascade of events leading to myocardial dysfunc- tion. For example, Pseudornonas aeruginosa exotoxin A impairs contractile function in both isolated myocytes [23] and isolated rat hearts [24].
Cytokines: tumour necrosis factor-alpha, interleukin-1, -2 and -6
Inflammatory cytokines appear to have a biphasic pat- tern of effect, with a rapid direct influence on myocar- dium, followed by delayed effects secondary to the in- duction of protein isoforms such as inducible nitric oxide synthase (NOS2) and cyclo-oxygenase (COX2) that are not normally expressed in cardiac tissue. Both NOS2 and COX2 may alter myocardial contractile func- tion, as discussed later. Some of the acute effects of cy- tokines may be mediated by activation of constitutively present nitric oxide synthase (NOS3). For example, ex- posure of isolated hamster papillary muscles to either tumour necrosis factor-alpha (TNFa), interleukin-6 or interleukin-2, or of isolated guinea pig and rabbit ventri- cular myocytes to TNFa rapidly induced a negative ino- tropic effect, which was blocked by NOS inhibitors and restored by L-arginine (the substrate for the production of NO) [25, 26]. However, cytokines may also exert acute effects independent of NO. For example, both TNFa and IL-1/3 were reported to cause an acute NO- independent reduction in intracellular calcium current in rat ventricular myocytes [27, 28].
Experimental in vivo studies also support a role for cytokines in the development of myocardial dysfunction in septic shock. Intravenous infusion of TNFa into ani- mals induces the haemodynamic characteristics of sepsis with associated myocardial depression [29, 30]. Expo- sure of animals to live bacteria induces septic shock,
which can be prevented by pretreatment with anti- TNFa antibodies [31]. Endotoxin induces expression of TNFa mRNA and protein in endothelial cells, smooth muscle cells and cardiac myocytes in isolated feline hearts and ventricular myocytes [32]. Moreover, in the latter study, superfusate from endotoxin-treated isola- ted hearts had a negative inotropic effect on isolated cardiac myocytes, which was blocked by anti-TNFc~ an- tibodies [32].
Plasma levels of TNFa are elevated in patients with septic shock, compared to those with sepsis without shock or other forms of circulatory impairment (e. g. cardiogenic shock) [33]. In addition, TNFa mRNA and protein have been detected in human myocardium in other conditions with impaired LV function, such as di- lated cardiomyopathy [34, 35]. Plasma levels of TNFa are also elevated in patients with heart failure, although circulating soluble TNFa receptors, whose physiological role is unknown, are also present in such patients [36].
Platelet activating factor (PAF)
PAF is another important mediator of the inflammatory response which is produced by a variety of different cell types, including endothelial cells and macrophages fol- lowing exposure to endotoxin. Plasma levels are in- creased in patients with sepsis [37]. PAF has been postu- lated to be important in the pathogenesis of myocardial depression because it is known to have negative inotro- pic effects in different animal models [38]. Furthermore, PAF receptor antagonists have been shown to prevent some of the haemodynamic effects of endotoxin in ex- perimental models [39, 40].
Cyclo-oxygenase and prostaglandins
Abnormalities of the synthesis of prostaglandins and thromboxane have been postulated to contribute to the septic shock syndrome [1]. Prostaglandin is produced by the enzyme cyclo-oxygenase (COX), which has two isoforms, COX1, which is constitutively expressed, and COX2, which can be induced by endotoxin and other in- flammatory mediators [41]. Although inhibitors of COX, including non-steroidal anti-inflammatory agents, have been beneficial in some animal models of septic shock, detailed study has failed to show any effect on the myocardial depression in porcine endotoxaemia [42]. Furthermore, a randomised double-blind clinical trial of ibuprofen in patients with severe sepsis showed no reduction in the incidence of septic shock and no im- provement in survival [43].
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Endothelial-derived factors
Recent studies have demonstrated that the release of cardioactive factors (e. g. NO and endothelin) by endo- thelial cells contributes to paracrine regulation of myo- cardial function [15, 44, 45]. Hypoxic endothelium has recently been shown to release a novel, and as yet uni- dentified, substance which inhibits myocardial cross- bridge cycling via inhibition of actin-activated cardiac myosin adenosine triphosphatase [46]. Abnormal re- lease of these substances by endothelial cells in patholo- gical states could therefore contribute to myocardial dysfunction. However, apart from NO, a possible role for endothelially derived substances in the myocardial dysfunction of sepsis remains speculative at this stage.
Nitric oxide (NO) and the heart
In recent years, there has been enormous interest in a possible role of NO in the pathophysiology of septic shock. The induction of NOS2 and consequent "over- production" of NO appears to be an important factor re- sponsible for the systemic vasodilatation and hypoten- sion observed in septic shock. However, its role with re- spect to cardiac dysfunction is less clear. It is relevant in this context to consider first the physiological effects of NO on myocardial function.
In the heart, endothelial-type NO synthase (NOS3) is constitutively expressed in coronary vascular endo- thelial cells, endocardial endothelial cells and cardiac myocytes [47]. NOS2 does not appear to be normally ex- pressed in most cell types, but is readily induced in car- diac myocytes, endothelial and endocardial cells by ex- posure to different cytokines [48, 49]. NOS3 has several different effects on myocardial contractile function. NO derived from coronary endothelial NOS3 has been shown to modulate cardiac myocyte function in a para- crine manner in a variety of different models, ranging from isolated myocytes and papillary muscles to isolated "working hearts" and human patients in vivo [15, 50]. It selectively enhances myocardial relaxation with rela- tively little effect on maximal rates of force generation and also increases diastolic compliance. In human sub- j ects given intracoronary infusions of substance P (to re- lease endothelium-derived NO) or low doses of sodium nitroprusside (an exogenous NO donor), an earlier on- set of LV relaxation and an increase in LV diastolic dis- tensibility (i. e. increased LV end-diastolic volume with- out an increase in LV end-diastolic pressure) were ob- served [51, 52].
NO also appears to modulate myocardial perfor- mance via a number of other physiological regulatory mechanisms. It antagonises the positive inotropic effect of beta-adrenergic agonists in a number of different ani- mal models [53] and in patients [54]. In isolated guinea
pig hearts, endogenous NO augments the Frank-Starling response; inhibition of NOS reduced the increase in car- diac output seen in response to elevation of preload, an effect restored by L-arginine, the precursor of NO [55]. Enhanced force production in response to increased stimulation frequency is a characteristic property of most mammalian cardiac muscle. In the hamster this "force-frequency" relationship is negative but can be converted to positive by inhibiting NO [56]. Recent in vitro data also suggest that NO may also be involved in the regulation of heart rate [57, 58].
Many of these effects of NO are mediated via activa- tion of soluble guanylate cyclase and the resultant eleva- tion of intracellular 3'5'-cylcic guanosine monophos- phate (cGMP), although other important effects may be cGMP independent [59]. The effects of NO on myo- cardial contraction and diastolic function are thought to be mediated via a cGMP-induced reduction in myo- filament response to calcium [26, 60]. cGMP also has several other effects in the myocardium which have been extensively reviewed [61]. cGMP-mediated stimu- lation of cyclic adenosine monophosphate (cAMP) phosphodiesterase activity (thereby reducing cAMP le- vels) underlies the effect of NO to attenuate/3-adrener- gic responses [47].
Role of NO in cardiac dysfunction of sepsis
Several lines of evidence suggest that NOS2 may have an important role in the pathogenesis of cardiac dys- function in sepsis. NOS2 activity and/or mRNA have been demonstrated in cardiac endothelial cells [49] and isolated cardiac myocytes [47, 48] following in vitro ex- posure to a variety of cytokines, including TNFc~ IL-1/3 and interferon-y. NOS2 is also expressed in these cells in animals injected with endotoxin [62, 63].
The precise role of NOS in mediating cytokine-in- duced cardiac dysfunction is, however, less clear. Sever- al in vitro studies have shown that cytokine-induced myocardial depression may be attributed to NOS2. In cultured rat ventricular myocytes incubated with super- natant from "endotoxin-activated" macrophages, the in- otropic response to isoproterenol was reduced, an effect reversed by an NOS inhibitor, N°-monomethyl-L-argi - nine L-NMMA [64]. Similarly an NO-dependent mech- anism was involved in the negative inotropic effect ob- served in isolated ferret papillary muscles exposed to IL-1/3 [65]. Ventricular myocytes isolated from guinea pigs injected with endotoxin had reduced fractional shortening compared to control myocytes, an effect also reversed by NOS inhibitors [62]. A selective NOS2 inhibitor, L-canavanine, was shown to have some benefi- cial haemodynamic effects in an endotoxaemic rat mod- el [66]. Knockout mice deficient in the gene for NOS2 have been shown to be less susceptible to lipopolysac-
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charide-induced shock than normal mice, although they were more susceptible to other aspects of infection [67]. However, another study performed using ventricular myocytes isolated from endotoxaemic guinea pigs re- ported no change in NOS activity and no effect of NOS inhibitors on the depressed contractility [68]. NOS inhi- bitors have also been reported not to block the negative inotropic effects of TNF~ in isolated cat myocytes [27], nor the endotoxin-induced myocardial depression in an isolated rat heart model [69]. The reasons for these con- flicting results are not clear, but may include differences between species and differing experimental conditions. It is also likely that the activity of expressed NOS2 may be influenced by the availability of substrate (L-argi- nine) and co-factors (e. g. tetrahydrobiopterin, BH4). In- deed, it is known that cytokines induce the expression of L-arginine transporters, guanosine triphosphate (GTP)- cyclohydrolase I (the enzyme that catalyses formation of BH4) and arginosuccinate synthase and lyase (the en- zymes responsible for intracellular synthesis of arginine from citrulline) [70].
NO: a double-edged sword?
The ubiquitous nature of the NOS2 response to sepsis suggests that there must be beneficial effects of NOS2 induction. NO has antimicrobial and antiviral effects, and is one of the mediators used by macrophages for killing foreign organisms [71]. NO also acts as a free rad- ical scavenger, and thus may limit the oxidative damage to cells from these highly reactive molecules. In the heart, NO may mediate the apparently beneficial LV di- latation which allows the ventricle to utilise the Frank- Starling mechanism. Limitation of the effects of gross /3-adrenergic stimulation and augmentation of coronary flow are other mechanisms which may be protective and improve cardiac function. In view of this complex array of effects, simple generalised inhibition of NO would seem unlikely to be a rational therapeutic approach.
On the other hand, gross overproduction of NO by NOS2 may have additional deleterious effects on myo- cardial function to those discussed above. NO inhibits several enzymes involved in mitochondrial respiration, via cyclic GMP-independent mechanisms, thus reducing myocardial oxygen consumption, and adenosine tripho- sphate production within myocardium [72, 73]. NO also combines with superoxide free radicals to form peroxy- nitrite (ONOO-), which itself can cause cellular damage [74]. Recent studies indicate that NO may also trigger apoptosis (or programmed cell death) in cardiac myo- cytes, which may be an important mechanism for myo- cardial dysfunction [75].
Therapy for cardiac dysfunction in septic shock
The mainstay of treatment of septic shock and cardiac depression at present remains circulatory support. Hy- povolaemia should be corrected with appropriate fluid replacement and guided by monitoring PCWP to ensure adequate filling pressures and optimal use of the "pre- load reserve". Inappropriate systemic vasodilatation may be treated by vasoconstrictors, such as noradrena- line, although it is important to avoid excessive drops in stroke output due to afterload mismatch. Catechola- mine-based positive inotropic agents such as dobuta- mine and adrenaline may be needed. Attention should also be given to the treatment of arrhythmias and meta- bolic imbalance, which may both contribute to reduced cardiac function. General measures such as ensuring adequate oxygenation and providing renal support, nu- trition and appropriate antibiotic therapy are all vital.
Alongside the increase in knowledge regarding the pathogenesis of septic shock has come the development of specific therapies targeted against the different me- diators thought to be involved. Results of therapeutic trials with respect to overall mortality have been disap- pointing to date. The effects of these interventions on cardiac dysfunction have not yet been studied in detail. An improvement in blood pressure may be due to rever- sal of systemic vasodilatation rather than any direct car- diac effect. The first target for immunotherapy was en- dotoxin, but trials of anti-endotoxin antibodies failed to demonstrate on overall benefit [76, 77]. Some early small studies reported an improvement in cardiac func- tion in septic patients treated with anti-TNFa antibo- dies [78, 79], but larger clinical trials of different anti- TNFa antibodies have been disappointing, with no im- provement in overall survival [80, 81]. There has been one reported trial of a PAF antagonist in human septic shock, which did not show any haemodynamic benefit [82]. One possible reason for the failure of these strate- gies is that these inflammatory cytokine responses are likely to play a role in protecting the host and eradicat- ing infection, as well as exerting certain deleterious ef- fects. Therefore generalised blockade may fail to be beneficial or even have a net harmful effect. This was seen in a recent trial of TNF receptor fusion protein in sepsis, which blocked the action of TNFa but resulted in an increase in mortality [83]. It is also possible that in- hibition of individual components of the complex re- sponses triggered in the septic shock syndrome will be unsuccessful. However, non-specific inhibition of the immune response with corticosteroids has also been in- effective in improving outcome of septic shock [84].
Several small clinical trials have reported the haemo- dynamic effects of blockade of the NO pathway in pa- tients with septic shock. Non-specific NOS inhibitors appear to be effective at reversing some of the inap- propriate systemic vasodilatation, thus increasing sys-
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temic vascular resistance and mean arterial pressure [85, 86]. Infusion of methylene blue (a non-specific inhibitor of guanylate cyclase) has been reported to have favour- able haemodynamic and myocardial effects in patients with septic shock, increasing systemic vascular resis- tance, mean arterial pressure and LVSWI [87]. In leuco- cytopenic patients with septic shock, another NOS inhi- bitor, Na-nitro-L-arginine methyl ester L-NAME, in- creased blood pressure, while maintaining cardiac out- put, without affecting preload or heart rate [88]. Both these studies provide indirect evidence of a positive ino- tropic effect of NO blockade since, in the absence of an increase in myocardial contractility, the increase in afterload would have been expected to reduce stroke volume. However, other groups have reported a fall in cardiac output with increased systemic vascular resis- tance consequent upon NOS inhibition [86]. Thus, the direct myocardial effects of NOS inhibition in patients with "septic" cardiac dysfunction require further de- tailed study, as do the effects on mortality.
Possible strategies for future treatment include the development of more effective neutralising antibodies and their possible local delivery to different organ sys- tems; the use of selective NOS2 inhibitors, or TNFa re- ceptor antagonists; the use of combination therapies, and/or tailored regimens for different stages of the shock syndrome.
Conclusions
Myocardial depression is a common complication of septic shock, although it may not always be clinically ap- parent because of alterations in heart rate and cardiac loading conditions, particularly the reduction in after- load. The myocardial response to sepsis appears to be systolic depression and diastolic dilatation of the LV, the latter probably serving to maintain stroke volume via the Frank-Starling mechanism. Effective use of this mechanism requires adequate cardiac fillingl (i.e. c o r -
rection of hypovolaemia). Patients who fail to exhibit LV dilatation have reduced LVEF and LVSWI and ap- pear to have a worse prognosis. Questions concerning pathogenesis that need to be addressed include: what are the causes of the myocardial depression and what determines the LV response?
Some of the answers to the first question are now emerging. Endotoxin is capable of triggering myocar- dial depression via the induction of a cascade of media- tors. TNF(z appears to be important, although other substances are involved, including PAF and IL-1 ft. These cytokines exert both acute negative inotropic ef- fects and delayed effects secondary to induction of new proteins in the myocardium. The induction of NOS2, capable of producing high local levels of NO, may play a role in the development of myocardial de- pression, although most of the evidence in support of this hypothesis is based on in vitro data. It seems likely that induction of NOS2 may be a double-edged sword with both beneficial and deleterious effects. In particu- lar, NO has antimicrobial and antiviral effects and may also contribute to the acute increase in LV diastolic compliance. However, the downside of excessive NOS2 induction may be systolic depression and myo- cyte damage.
Despite these advances in the understanding of the pathogenesis of cardiac dysfunction in septic shock, the results of new treatment regimens have so far been dis- appointing. Possibly too much emphasis has been placed on identifying the triggers of septic shock, when the clin- ical problem is usually one of established sepsis. In addi- tion, it is unlikely that targeting a single component of a multifactorial disorder will be effective. More attention needs to be paid to developing better indices to monitor cellular dysfunction in the syndrome, ways of reversing multiple organ failure and identification of the impor- tant cellular signals that promote continuing dysfunc- tion. In the future we may hope for an improved arsenal of specific therapies, which could be tailored according to the individual needs of a patient with septic shock.
References
1. Parrillo JE (1993) Pathogenetic me- chanisms of septic shock. N Engl J Med 28:1471-1477
2. Bone RC (1996) Toward a theory re- garding the pathogenesis of the system- ic inflammatory response syndrome: what we do and do not know about cy- tokine regulation. Crit Care Med 24: 163-172
3. Parker MM, Shelhamer JH, Bacharach SL, Green MV, Natanson C, Frederick TM, Damske BA, Parrillo JE (1984) Profound but reversible myocardial de- pression in patients with septic shock. Ann Intern Med 100:483-490
4. Ellrodt AG, Riedinger MS, Kimchi A, Berman DS, Maddahi J, Swan HJC, Murata GH (1985) Left ventricular per- formance in septic shock: reversible segmental and global abnormalities. Am Heart J 110:402-409
5. Ognibene FR Parker MM, Natanson C, Shelhamer JH, Parrillo JE (1988) De- pressed left ventricular performance; response to volume infusion in patients with sepsis and septic shock. Chest 93: 903-910
6. Natanson C, Danner RL, Fink MR MacVittie TJ, Walker RI, Conklin JJ, Parrillo JE (1988) Cardiovascular per- formance with Escherichia coli challen- ges in a canine model of human sepsis. Am J Physio1254:H558-H569
293
7. Parker MM, Suffredini AF, Natanson C, Ognibene FR Shelhamer JH, Parrillo JE (1989) Responses of left ventricular function in survivors and nonsurvivors of septic shock. J Crit Care 4:19-25
8. Parker MM, McCarthy KE, Ognibene FR Parrillo JE (1990) Right ventricular dysfunction of dilatation, similar to left ventricular changes, characterize the cardiac depression of septic shock in hu- mans. Chest 97:126-131
9. Poelaert J, Declerck C, Vogelaers D, Colardyn F, Visser CA (1997) Left ven- tricular systolic and diastolic function in septic shock. Intensive Care Med 23: 553-560
10. Cunnion RE, Schaer GL, Parker MM, Natanson C, Parrillo JE (1986) The cor- onary circulation in human septic shock. Circulation 73:637-644
11. Dhainaut J-F, Huyghebaert M-F, Mon- sallier JF, Lefevre G, Dall'Ava-Santucci J, Brunet F, Villemont D, Carli A, Raichvarg D (1987) Coronary hemody- namics and myocardial metabolism of lactate, free fatty acids, glucose, and ke- tones in patients with septic shock. Cir- culation 75:533-541
12. Van Lambalgen AA, van Kraats AA, Mulder ME Teerlink T, van den Bos GC (1994) High energy phosphates in heart, liver, and skeletal muscle of en- dotoxemic rats. Am J Physiol 266: H1581-H1587
13. Hinshaw LB (1996) Sepsis/septic shock: participation of the microcirculation: an abbreviated review. Crit Care Med 24: 1072-1078
14. Goddard CM, Allard ME Hogg JC, Walley KR (1996) Myocardial morpho- metric changes related to decreased contractility after endotoxin. Am J Phy- sio1270:H1446-H1452
15. Shah AM, Grocott-Mason RM, Pepper CB, Mebazaa A, Henderson AH, Lewis MJ, Paulus WJ (1996) The cardiac en- dothelium: cardioactive mediators. Prog Cardiovasc Dis 39:263-284
16. Lefer A, Rovetto M (1970) Influence of a myocardial depressant factor on phy- siologic properties of cardiac muscle. Proc Soc Exp Biol 134:269-273
17. Carli A, Auclair MC, Benassayag C, Nunez E (1981) Evidence for an early lipid soluble cardiodepressant factor in rat serum after a sublethal dose of en- dotoxin. Circ Shock 8:301-312
18. Parrillo JE, Burch C, Shelhamer JH, Parker MM, Natanson C, Schuette W (1985) A circulating myocardial depres- sant substance in humans with septic shock. J Clin Invest 76:1539-1553
19. Kumar A, Thota V, Dee L, Olson J, Uretz E, Parrillo JE (1996) Tumour ne- crosis factor alpha and interleukin i beta are responsible for in vitro myo- cardial cell depression induced by hu- man septic shock serum. J Exp Med 183:949-958
20. Suffredini AF, Fromm RE, Parker MM, Brenner M, Kovacs JA, Wesley RA, Parrillo JE (1989) The cardiovascular response of normal humans to the ad- ministration of endotoxin. N Engl J Med 321:280-287
21. Danner RL, Elin RJ, Hoseini JM, Wes- ley RA, Reilly JM, Parrillo JE (1988) Endotoxemia in human septic shock. Chest 99:169-175
22. Granton JT, Goddard CM, Allard ME van Eeden S, Walley KR (1997) Leuko- cytes and decreased left ventricular contractility during endotoxaemia in rabbits. Am J Respir Crit Care Med 155:1977-1983
23. Muller-Werdan U, Pfeifer A, Hubner G, Seliger C, Reithmann C, Rupp H, Wer- dan K (1997) Partial inhibition of pro- tein synthesis by Pseudomonas exotox- in A deranges catecholamine sensitivity of cultured rat heart myocytes. J Mol Cell Cardiol 29:799-811
24. Kwiatkowska-Patzer B, Patzer JA, Hel- ler LJ (1993) Pseudomonas aeruginosa exotoxin A enhances automaticity and potentiates hypoxic depression of isola- ted rat hearts. Proc Soc Exp Biol Med 202:377-383
25. Finkel MS, Oddis CV, Jacob TD, Wat- kins SC, Hattler BG, Simmons RL (1992) Negative inotropic effects of cy- tokines on the heart mediated by nitric oxide. Science 257:387-389
26. Goldhaber JL, Kim KH, Natterson PD, Lawrence T, Yang E Weiss JN (1996) Effects of TNF-a on [Ca>]; and con- tractility in isolated adult rabbit ventri- cular myocytes. Am J Physiol 271: H1449-H1455
27. Yokoyama T, Vaca L, Rossen RD, Dur- ante W, Hazarika R Mann DL (1993) Cellular basis for the negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian heart. J Clin In- vest 92:2303-2312
28. Liu S, Schreur KD (1995) G protein- mediated suppression of L-type Ca cur- rent by interleukin-1/3 in cultured rat ventricular myocytes. Am J Physiol 268:C339-C349
29. Tracey K J, Beutler B, Lowry SF, Merry- weather J, Wolpe S, Milsark IW, Hariri R J, Fahey TJ, Zentella A, Albert JD, Shires T, Cerami A (1986) Shock and tissue injury induced by recombinant human cachectin. Science 234:470-474
30. Natanson C, Eichenholz PW, Danner RL, Eichacker PQ, Hoffman WD, Kuo GC, Banks SM, MacVittie TJ, Parrillo JE (1989) Endotoxin and tumor necro- sis factor challenges in dogs simulate the cardiovascular profile of human septic shock. J Exp Med 169:823-832
31. Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, Lowry SF, Cera- mi A (1987) Anti-cachectin/TNF mono- clonal antibodies prevent septic shock during lethal bacteraemia. Nature 330: 662-664
32. Kapadia S, Lee J, Torre-Amione G, Birdsall HH, Ma TS, Mann DL (1995) Tumor necrosis factor-alpha gene and protein expression in adult feline myo- cardium after endotoxin administra- tion. J Clin Invest 96:1042-1052
33. de Werra I, Jaccard C, Corradin SB, Chiolero R, Yersin B, Gallati H, Assi- cot M, Bohuon C, Baumgartner J-D, Glausser MR Heumann D (1997) Cyto- kines, nitrite/nitrate, soluble tumor ne- crosis factor receptors, and procalcito- nin concentrations: comparisons in pa- tients with septic shock, cardiogenic shock and bacterial pneumonia. Crit Care Med 25:607-613
34. Habib FM, Springall DR, Davies GJ, Oakley CM, Yacoub MH, Polak JM (1996) Tumor necrosis factor and indu- cible nitric oxide synthase in dilated car- diomyopathy. Lancet 347:1151-1155
35. Satoh M, Nakumura M, Tamura G, Ma- kita S, Segawa I, Tashiro A, Satodate R, Hiramori K (1997) Inducible nitric oxide synthase and tumor necrosis fac- tor-alpha in myocardium in human dila- ted cardiomyopathy. J Am Coll Cardiol 29:716-724
36. Ferrari R, Bachetti T, Confortini R, Opasich C, Febo O, Corti A, Cassani G, Visioli O (1995) Tumor necrosis fac- tor soluble receptors in patients with various degrees of congestive heart fail- ure. Circulation 92:1479-1486
37. Diez FL, Nieto ML, Fernandez-Gallar- do S, Gijon MA, Crespo MS (1989) Oc- cupancy of platelet receptors for plate- let-activating factor in patients with septicaemia. J Clin Invest 83:1733-1740
38. Kenzora JL, Perez JE, Bergmann SR, Lange LG (1984) Effects of acetyl gly- ceryl ether of phosphorylcholine (plate- let activating factor) on ventricular pre- load, afterload, and contractility in dogs. J Clin Invest 74:1193-1203
294
39. Yamanaka S, Iwao H, Yukimura T, Kim S, Miura K (1993) Effect of the platelet- activating factor antagonist, TCV-309, and the cyclo-oxygenase inhibitor, ibu- profen, on the haemodynamic changes in canine experimental endotoxic shock. Br J Pharmacol 110:1501-1507
40. Herbertson MJ, Werner HA, Walley KR (1997) Platelet-activating factor an- tagonism improves ventricular contrac- tility in endotoxaemia. Crit Care Med 25:221-226
41. Liu SF, Newton R, Evans TW, Barnes PJ (1996) Differential regulation of cy- clo-oxygenase-1 and cyclo-oxygenase-2 gene expression by lipopolysaccharide treatment in the rat. Clin Sci 90: 301- 306
42. Herbertson MJ, Werner HA, Studer W, Russell JA, Walley KR (1996) De- creased left ventricular contractility during porcine endotoxemia is not pre- vented by ibuprofen. Crit Care Med 24: 815-819
43. Bernard GR, Wheeler AR Ibuprofen in Sepsis Study Group (1997) The effects of ibuprofen on the physiology and sur- vival of patients with sepsis. N Engl J Med 336:912-918
44. Shah AM, Mebazaa A, Wetzel RC, La- katta EG (1994) Novel cardiac myofila- ment desensitizing factor released by endocardial and vascular endothelial cells. Circulation 89:2492-2497
45. Pepper CB, Lang D, Lewis MJ, Shah AM (1995) Endothelial inhibition of myofilament calcium response in intact cardiac myocytes. Am J Physiol 269: H1538-H1544
46. Shah AM, Mebazaa A, Yang Z-K, Cuda G, Lankford EB, Pepper CB, Sollott S J, Sellers JR, Robotham JL, Lakatta EG (1997) Inhibition of myocardial cross- bridge cycling by hypoxic endothelial cells. A potential mechanism for match- ing oxygen supply and demand? Circ Res 80:688-698
47. Kelly RA, Balligand J-L, Smith TW (1996) Nitric oxide and cardiac contrac- tile function. Circ Res 79:363-380
48. Schulz R, Nava E, Moncada S (1992) Induction and potential biological rele- vance of a Ca2+-independent nitric oxide synthase in the myocardium. Br J Pharmacol 105:575-580
49. Balligand J-L, Ungureanu-Longrois D, Simmons WW, Kobzik L, Lowenstein CJ, Lamas S, Kelly RA, Smith TW, Mi- chel T (1995) Induction of NO synthase in rat cardiac microvascular endothelial cells by IL-1/3 and IFN- 7. Am J Physiol 268:H1293-H1303
50. Grocott-Mason RM, Anning R Evans HG, Lewis MJ, Shah AM (1994) Modu- lation of left ventricular relaxation in isolated ejecting guinea pig heart by en- dogenous nitric oxide. Am J Physiol 267:H1804-H1813
51. Paulus WJ, Vantrimpont PJ, Shah AM (1994) Acute effects of nitric oxide on left ventricular relaxation and diastolic distensibility in man. Circulation 89: 2070-2078
52. Paulus WJ, Vantrimpont PJ, Shah AM (1995) Paracrine coronary endothelial control of left ventricular function in humans. Circulation 92:2119-2126
53. Balligand J-L, Kobzik L, Han X, Kaye DM, Belhassen L, O'Hara DS, Kelly RA, Smith TW, Michel T (1995) Nitric oxide-dependent parasympathetic sig- naling is due to activation of constitu- tive endothelial (type III) nitric oxide synthase in cardiac myocytes. J Biol Chem 270:14582-14586
54. Bartunek J, Shah AM, Vanderheyden M, Paulus WJ (1997) Dobutamine en- hances cardiodepressant effects of re- ceptor-mediated coronary endothelial stimulation. Ciruclation 95:90-96
55: Prendergast BD, Sagach VF, Shah AM (1997) Endogenous nitric oxide aug- ments the Frank-Starling response in the isolated heart. Circulation 96: 1320-1329
57. Han X, Shimoni Y, Giles WR (1994) An obligatory role for nitric oxide in auto- nomic control of mammalian heart rate. J Physio1476:309-314
58. Musialek R Lei M, Brown HF, Paterson DJ, Casadei B (1997) Nitric oxide can increase heart rate by stimulating the hyperpolarization-activated inward cur- rent, If. Circ Res 81:60-68
59. Stamler JS, Singel D J, Loscalzo J (1992) Biochemistry of nitric oxide and its re- dox-activated forms. Science 258: 1898- 1902
60. Shah AM, Spurgeon H, Sollott S J, Talo A, Lakatta EG (1994) 8-bromo cyclic GMP reduces the myofilament re- sponse to calcium in intact cardiac myo- cytes. Circ Res 74:970-978
62. Brady AJB, Poole-Wilson PA, Harding SE, Warren JB (1992) Nitric oxide with- in cardiac myocytes reduces their con- tractility in endotoxemia. Am J Physiol 263:H1963-H1966
63. Luss H, Watkins SC, Freeswick PD, Imro AK, Nussler AK, Billiau TR, Sim- mons RL, del Nido PJ, McGowen FX Jr (1995) Characterization of inducible ni- tric oxide synthase expression in endo- toxemic rat cardiac myocytes in vivo and following cytokine exposure in vi- tro. J Mol Cell Cardio127:2015-2029
64. Balligand J-L, Ungureanu D, Kelly RA, Kobzik L, Pimental D, Michel T, Smith TW (1993) Abnormal contractile func- tion due to induction of nitric oxide synthesis in rat cardiac myocytes fol- lows exposure to activated macro- phage-conditioned medium. J Clin In- vest 91:2314-2319
65. Evans HG, Lewis MJ, Shah AM (1993) Interleukin-1/3 modulates mycardial contraction via dexamethasone-sensi- tive production of nitric oxide. Cardio- vasc Res 27:1486-1490
66. Fishman D, Liaudet L, Lazor R, Perret CH, Feihl F (1997) L-canavanine, an in- hibitor of inducible nitric oxide syn- thase, improves venous return in endo- toxemic rats. Crit Care Med 25:469-475
67. MacMicking JD, Nathan C, Hom G, Chartrain N, Fletcher DS, Trumbauer M, Stevens K, Xie Q, Sokol K, Hutchin- son N, Chen H, Mudgett JS (1995) Al- tered responses to bacterial infection and endotoxic shock in mice lacking in- ducible nitric oxide synthase. Cell 81: 641-650
68. Keller RS, Jones J J, Kim KF, Myers PR, Adams HR, Parker JL, Rubin LJ (1995) Endotoxin-induced myocardial dys- function: is there a role for nitric oxide. Shock 4:338-344
69. Klabunde RE, Coston AF (1995) Nitric oxide synthase inhibition does not pre- vent cardiac depression in endotoxic shock. Shock 3:73-78
70. Simmons WW, Ungureanu-Longrois D, Smith GK, Smith TW, Kelly RA (1996) Glucocorticoids regulate inducible ni- tric oxide synthase (NOS2) by inhibit- ing tetrahydrobiopterin synthesis and L-arginine transport. J Biol Chem 271: 23928-23937
71. Nathan C (1995) Natural resistance and nitric oxide. Cell 82:873-876
72. Oddis CV, Finkel MS (1995) Cytokine- stimulated nitric oxide production in- hibits mitochondrial activity in cardiac myocytes. Biochem Biophys Res Comm 213:1002-1009
73. Xie YW, Shen W, Zhao G, Xu X, Wolin MS, Hintze T (1996) Role of endothe- lium-derived nitric oxide in the modula- tion of canine myocardial mitochon- drial respiration in vitro. Circ Res 79: 381-387
295
74. Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA (1990) Ap- parent hydroxyl radical production by peroxynitrite: implications for endothe- lial injury from nitric oxide and super- oxide. Proc Natl Acad Sci USA 87: 1620-1624
75. Pinsky D J, Cai B, Yang X, Rodriguez C, Sciacca RR, Cannon PJ (1995) The le- thal effects of cytokine-induced nitric oxide on cardiac myocytes are blocked by nitric oxide synthase antagonism or transforming growth factor/3. J Clin In- vest 95:677-685
76. Ziegler EJ, Fisher CJ, Sprung CL, HA- 1A Sepsis Study Group (1991) Treat- ment of gram-negative bacteremia and septic shock with HA-1A human mono- clonal antibody against endotoxin - a randomized, double-blind, placebo- controlled trial. N Engl J Med 324: 429-436
77. Greenman RL, Schein RM, Martin MA, XOMA Sepsis Study Group (1991) A controlled clinical trial of E5 murine monocloncal IgM antibody to endotoxin in the treatment of gram- negative sepsis. JAMA 266:1097-1102
78. Exley AR, Cohen J, Buurman W, Owen R, Hanson G, Lumley J, Aulakh JM, Bodmer M, Riddell A, Stephens S, Per- ry M (1990) Monoclonal antibody to TNF in severe septic shock. Lancet 353: 1275-1277
79. Vincent JL, Bakker J, Marcecaux G, Schandene L, Kahn RJ, Dupont E (1992) Administration of anti-TNF an- tibody improves left ventricular func- tion in septic shock patients. Results of a pilot study. Chest 101:810-815
80. Reinhart K, Wiegand-Lohnert C, Grim- minger E Kaul M, Withington S, MAK 195F Sepsis Study Group (1996) Assess- ment of the safety and efficacy of the monoclonal anti-tumor necrosis factor antibody-fragment, MAK 195F, in pa- tients with sepsis and septic shock: a multicenten randomised, placebo-con- trolled, dose ranging study. Crit Care Med 24:733-742
81. Cohen J, Carlet J, INTERSEPT Study Group (1996) An international multi- center, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-a in patients with sepsis. Crit Care Med 24:1431-1440
82. Dhainaut J-F, Tenaillon A, Le Tutzo Y, BN 52021 Sepsis Study Group (1994) Platelet-activating receptor antagonist BN 52021 in the treatment of severe sepsis: a randomised, double-blind, pla- cebo-controlled, multicenter clinical trial. Crit Care Med 22:1720-1728
83. Fisher CJ, Agosti JM; Opal SM, Soluble TNF Receptor Sepsis Study Group (1996) Treatment of septic shock with the tumor necrosis factor receptor: Fc fusion protein. N Engl J Med 334: 1697-1702
84. Bone RC, Fisher CJ, Clemmer TR Me- thylprednisolone Severe Sepsis Study Group (1987) A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 317:653-658
85. Lorente JA, Landis L, de Pablo R, Re- nes E, Liste D (1993) L-arginine path- way in the sepsis syndrome. Crit Care Med 21:1287-1295
86. Petros A, Lamb G, Leone A, Moncada S, Bennett D, Vallance P (1994) Effects of a nitric oxide synthase inhibitor in humans with septic shock. Cardiovasc Res 28:34-39
87. Preiser J-C, Lejeune R Roman A, Car- lier E, Backer DD, Leeman M, Kahn R, Vincent J-L (1995) Methylene blue administration in septic shock: a clinical trial. Crit Care Med 23:259-264
88. Kiehl MG, Ostermann H, Meyer J, Kie- nast J (1997) Nitric oxide synthase inhi- bition by L-NAME in leukocytopaenic patients with severe septic shock. Inten- sive Care Med 23:561-566
