Inappropriate Sympathetic Activation at Onset of Septic Shock

Annane, Djillali; Trabold, Fabien; Sharshar, Tarek; Jarrin, I.; Blanc, Anne Sophie; Raphaël, Jean Claude; Gajdos, Philippe

doi:10.1164/ajrccm.160.2.9810073

Cited by 258 publications

(182 citation statements)

References 30 publications

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“…However, if these receptors are excessively stimulated or engaged over an extended period of time, myocardial damage by calcium overload and subsequent cell necrosis have been reported (82). Septic patients are known to be exhibit increased levels of catecholamines (55,83,84). These findings have been confirmed in various animal studies (85,86).…”

Section: β-Adrenergic Receptorsmentioning

confidence: 65%

“…Other reports linked high levels of circulating catecholamines with the onset of septic shock but found impaired sympathetic modulation on heart and vessels, suggesting that central autonomic regulatory impairment contributes to circulatory failure (55). Moreover, impaired function of the autonomic nervous system is associated with an increased risk for death from critical illness (56).…”

Section: Autonomic Dysfunctionmentioning

confidence: 99%

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Molecular Events in the Cardiomyopathy of Sepsis

Flierl

Rittirsch

Huber‐Lang

et al. 2008

Mol Med

108

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Septic cardiomyopathy is a well-described complication of severe sepsis and septic shock. However, the interplay of its underlying mechanisms remains enigmatic. Consequently, we constantly add to our pathophysiological understanding of septic cardiomyopathy. Various cardiosuppressive mediators have been discovered, as have multiple molecular mechanisms (alterations of myocardial calcium homeostasis, mitochondrial dysfunction, and myocardial apoptosis) that may be involved in myocardial dysfunction during sepsis. Finally, the detrimental roles of nitric oxide and peroxynitrite have been unraveled. Here, we describe our present understanding of systemic, supracellular, and cellular molecular mechanisms involved in sepsis-induced myocardial suppression. SYSTEMIC, SUPRACELLULAR MECHANISMS Decreased Coronary Blood FlowOne of the first suggestions was that reduced coronary perfusion in the septic heart might be responsible for a setting of global cardiac ischemia. This hypothesis was soon abandoned after direct measurements of coronary blood flow were obtained, showing no reduced, but rather increased, coronary blood flow (22,23). In later studies, however, increased levels of plasma troponin were observed and correlated with the severity of myocardial depression during sepsis and septic shock (24). Myocardial necrosis could not be observed in patients who died from septic shock (3,25), however, raising the question whether increases in troponin were due to cytokine-induced, transient increases in cardiomyocyte membrane permeability to troponin. To date, this remains to be determined. Alterations of MicrovasculatureThere is now increasing evidence that sepsis and septic shock leads to changes of the myocardial microvasculature. In a canine model of endotoxemia, maldistribution of heterogeneous coronary blood flow has been reported (26). These findings might be caused by endothelial swelling and nonocclusive intravascular fibrin deposits in the microvasculature (27). In parallel, activated cardiomyocytes from septic mice promoted transendothelial migration and activation of circulating neutrophils into the interstitium (28) where these cells may augment the sepsis-induced intracardial inflammation, and contribute to an increased vascular leakage, which has been described to also impair cardiac function and compliance secondary to myocardial edema (29,30). Yet, studies have failed to confirm cellular hypoxia in a murine sepsis model (31). Cardiosuppressing Circulating Proinflammatory MediatorsAnother hypothesis suggested circulating myocardium-depressing factors as the cause of septic cardiomyopathy (32). Parrillo et al. (33) confirmed the existence of a cardiodepressant substance by incubating isolated rat cardiomyocytes with serum obtained from septic shock patients, leading to decreased amplitude and velocity of cardiomyocyte shortening. Levels of cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and the complement anaphylatoxin, C5a, are known to be elevated in the circulation during sepsis an...

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Section: β-Adrenergic Receptorsmentioning

confidence: 65%

Section: Autonomic Dysfunctionmentioning

confidence: 99%

Molecular Events in the Cardiomyopathy of Sepsis

Flierl

Rittirsch

Huber‐Lang

et al. 2008

Mol Med

108

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“…This syndrome can affect all organ systems including the cardiovascular system [19], autonomic nervous system [20][21][22], endocrine system [23], metabolism [24] and bioenergetics [25]. During septic shock, circulatory compromise and mitochondrial damage [26][27][28] reduce intra-cellular ATP production and place the cells at risk of bio-energetic failure and cell death.…”

Section: Multiple Organ Dysfunction Syndromementioning

confidence: 99%

“…Early sepsis is characterized by high levels of circulating catecholamines [20,60,61] that derive from the autonomous nervous system, the gut [62], lymphocytes [63,64] macrophages [65] and neutrophils [66,67]. A major mechanism of sepsis-induced cardiac dysfunction is the attenuation of the adrenergic response at the cardiomyocyte level due to down-regulation of β-adrenergic receptors [68,69] and depression of post-receptor signaling pathways [70][71][72][73].…”

Section: Underlying Mechanismsmentioning

confidence: 99%

The Heart in Sepsis: From Basic Mechanisms to Clinical Management

Rudiger¹,

Singer

2013

CVP

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Septic shock is characterized by circulatory compromise, microcirculatory alterations and mitochondrial damage, which all reduce cellular energy production. In order to reduce the risk of major cell death and a diminished likelihood of recovery, adaptive changes appear to be activated. As a result, cells and organs may survive in a non-functioning hibernation-like condition. Sepsis-induced cardiac dysfunction may represent an example of such functional shutdown. Sepsis-induced myocardial dysfunction is common, corresponds to the severity of sepsis, and is reversible in survivors. Its mechanisms include the attenuation of the adrenergic response at the cardiomyocyte level, alterations of intracellular calcium trafficking and blunted calcium sensitivity of contractile proteins. All these changes are mediated by cytokines. Treatment includes preload optimization with sufficient fluids. However, excessive volume loading is harmful. The first line vasopressor recommended at present is norepinephrine, while vasopressin can be started as a salvage therapy for those not responding to catecholamines. During early sepsis, cardiac output can be increased by dobutamine. While early administration of catecholamines might be necessary to restore adequate organ perfusion, prolonged administration might be harmful. Novel therapies for sepsis-induced cardiac dysfunction are discussed in this article. Cardiac inotropy can be increased by levosimendan, istaroxime or omecamtiv mecarbil without greatly increasing cellular oxygen demands. Heart rate reduction with ivabradine reduces myocardial oxygen expenditure and ameliorates diastolic filling. Beta-blockers additionally reduce local and systemic inflammation. Advances may also come from metabolic interventions such as pyruvate, succinate or high dose insulin substitutions. All these potentially advantageous concepts require rigorous testing before implementation in routine clinical practice. While early administration of catecholamines might be necessary to restore adequate organ perfusion and pressure, prolonged administration might be harmful.Novel therapies for sepsis-induced cardiac dysfunction are discussed in this article. Cardiac inotropy can be increased by levosimendan, istaroxime or omecamtiv mecarbil without greatly increasing cellular oxygen demands. Heart rate reduction with ivabradine will reduce myocardial oxygen expenditure and ameliorate diastolic filling. Beta-blockers additionally reduce local and systemic inflammation. Advances may also come from metabolic interventions such as pyruvate, succinate or high dose insulin substitutions. However, all these potentially advantageous concepts require rigorous testing before implementation in routine clinical practice.-3 -Alain Rudiger & Mervyn Singer: The heart in sepsis

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“…Sepsis and septic shock. One of the most challenging subtypes of shock clinically is the septic shock, which is characterized by impaired functions of heart and vessel tone, despite high concentrations of circulating catecholamines (79). Yet, administration of catecholamines often becomes the choice of last resort to maintain blood pressure in patients with septic shock (80).…”

Section: Foolishly Unlocking Pandora's Box?mentioning

confidence: 99%

Catecholamines—Crafty Weapons in the Inflammatory Arsenal of Immune/Inflammatory Cells or Opening Pandora’s Box?

Flierl

Rittirsch

Huber‐Lang

et al. 2008

Mol Med

165

114

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It is well established that catecholamines (CAs), which regulate immune and inflammatory responses, derive from the adrenal medulla and from presynaptic neurons. Recent studies reveal that T cells also can synthesize and release catecholamines which then can regulate T cell function. We have shown recently that macrophages and neutrophils, when stimulated, can generate and release catecholamines de novo which, then, in an autocrine/paracrine manner, regulate mediator release from these phagocytes via engagement of adrenergic receptors. Moreover, regulation of catecholamine-generating enzymes as well as degrading enzymes clearly alter the inflammatory response of phagocytes, such as the release of proinflammatory mediators. Accordingly, it appears that phagocytic cells and lymphocytes may represent a major, newly recognized source of catecholamines that regulate inflammatory responses.

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Inappropriate Sympathetic Activation at Onset of Septic Shock

Cited by 258 publications

References 30 publications

Molecular Events in the Cardiomyopathy of Sepsis

Molecular Events in the Cardiomyopathy of Sepsis

The Heart in Sepsis: From Basic Mechanisms to Clinical Management

Catecholamines—Crafty Weapons in the Inflammatory Arsenal of Immune/Inflammatory Cells or Opening Pandora’s Box?

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