Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock

Sharshar, Tarek; Gray, Françoise; Grandmaison, Geoffrey Lorin de la; Hopklnson, Nicholas S; Ross, Ewen; Dorandeu, Anne; David, Olivier; Raphaël, Jean-Claude; Gajdos, Philippe; Annane, Djillali

doi:10.1016/s0140-6736(03)14899-4

Cited by 275 publications

(213 citation statements)

References 27 publications

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“…These changes are mediated by cytokines [74,75] and nitric oxide [76,77]. Blunting of the adrenergic response is probably enhanced by neuronal apoptosis in the cardiovascular autonomic centres [78], and by inactivation of catecholamines by reactive oxygen species [79].…”

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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Section: Underlying Mechanismsmentioning

confidence: 99%

The Heart in Sepsis: From Basic Mechanisms to Clinical Management

Rudiger¹,

Singer

2013

CVP

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“…The presence of mitochondria-dependent neuronal apoptosis in sepsis is supported by studies showing increased free intracellular Ca 2 + (Zhan et al, 1996) and enhanced cytoplasmic cytochrome c immunoreactivity (Messaris et al, 2004) in experimentally septic animals. Accordingly, apoptotic neurons with degenerating mitochondria have been observed in several brain regions of experimentally septic animals and deceased septic patients, including the cerebral cortex and hippocampus (Papadopoulos et al, 1999;Vereker et al, 2000;Semmler et al, 2005;Barichello et al, 2006;Orihuela et al, 2006;Kafa et al, 2010), the cerebellum (Messaris et al, 2004;Barichello et al, 2006), and some autonomic centers in the brain stem (Sharshar et al, 2003(Sharshar et al, , 2004.…”

Section: Apoptosismentioning

confidence: 99%

Neuro-oxidative-nitrosative stress in sepsis

Berg

Møller

Bailey

2011

J Cereb Blood Flow Metab

135

109

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Neuro-oxidative-nitrosative stress may prove the molecular basis underlying brain dysfunction in sepsis. In the current review, we describe how sepsis-induced reactive oxygen and nitrogen species (ROS/RNS) trigger lipid peroxidation chain reactions throughout the cerebrovasculature and surrounding brain parenchyma, due to failure of the local antioxidant systems. ROS/RNS cause structural membrane damage, induce inflammation, and scavenge nitric oxide (NO) to yield peroxynitrite (ONOO À ). This activates the inducible NO synthase, which further compounds ONOO À formation. ROS/RNS cause mitochondrial dysfunction by inhibiting the mitochondrial electron transport chain and uncoupling oxidative phosphorylation, which ultimately leads to neuronal bioenergetic failure. Furthermore, in certain 'at risk' areas of the brain, free radicals may induce neuronal apoptosis. In the present review, we define a role for ROS/RNS-mediated neuronal bioenergetic failure and apoptosis as a primary mechanism underlying sepsis-associated encephalopathy and, in sepsis survivors, permanent cognitive deficits.

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“…In response to the detection of systemic infl ammation, behavioral, neuroendocrine, and autonomic responses are generated including expression of immune receptors and cytokines, inducible nitric oxide synthase (iNOS), and prostaglandins leading to oxidative stress, mitochondrial dysfunction, and apoptosis [5,7,8].…”

Section: Infl Ammation and The Brainmentioning

confidence: 99%

Cerebral Perfusion in Sepsis

Burkhart

Siegemund

Steiner

2010

Intensive Care Medicine

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IntroductionSepsis, the host's reaction to infection, characteristically includes multi-organ dysfunction. Brain dysfunction is often one of the fi rst clinical symptoms in sepsis and may manifest as sepsis-associated delirium in up to 70% of patients [1,2], less often as focal defi cits or seizures [3]. As severely reduced global perfusion leading to hypotension, maldistribution of regional blood fl ow, and tissue hypoperfusion is a key feature of severe sepsis and septic shock, the question whether there is a link between cerebral perfusion and brain dysfunction in sepsis is obvious. However, clinical and experimental data on cerebral perfusion in sepsis are often inconsistent and most reports only include small numbers of animals or patients. We summarize the current literature on the eff ects of the infl ammatory response on cerebral per fusion and review the eff ects of altered cerebral perfusion on brain function in sepsis. Sepsis and the brainIn sepsis, the brain may be aff ected by many systemic disturbances, such as hypotension, hypoxemia, hyperglycemia, hypoglycemia, and organ dysfunction (e.g., increased levels of ammonia in liver dysfunction or urea in acute kidney injury). Direct brain pathologies, such as ischemic brain lesions, cerebral micro-and macrohemorrhage, microthrombi, microabscesses, and multifocal necrotizing leukencephalopathy, have also been described in histopathologic examinations [4,5]. However, in addition to these metabolic and `mechanical' eff ects on the brain, infl ammation by itself causes profound alterations in cerebral homeostasis in sepsis. Infl ammation and the brainSepsis at the outset causes a hyperinfl ammatory reaction, followed by a counteractive anti-infl ammatory reaction. Pro-and anti-infl ammatory cytokines are initially upregu lated. Despite its anatomical sequestration from the immune system by the blood-brain barrier, the lack of a lymphatic system, and a low expression of histocompatibility complex antigens, the brain is not isolated from the infl ammatory processes occurring elsewhere in the body. Th e circumventricular organs lack a bloodbrain barrier, and through these specifi c brain regions blood-borne cytokines enter the brain [5,6]. Th e circumventricular organs are composed of specialized tissue and are located in the midline ventricular system. Th ey consist of the organum vas culosum, the pineal body, the subcommissural organ, and the subfornical organ. Th ey also express components of the immune system (Toll-like receptors [TLR]), and receptors for cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α).A further mechanism by which the brain can detect systemic infl ammation is through aff erent vagal fi bers ending in the nucleus tractus solitarius, which senses visceral infl ammation through its axonal cytokine receptors. In response to the detection of systemic infl ammation, behavioral, neuroendocrine, and autonomic responses are generated including expression of immune receptors and cytokines, induci...

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Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock

Cited by 275 publications

References 27 publications

The Heart in Sepsis: From Basic Mechanisms to Clinical Management

The Heart in Sepsis: From Basic Mechanisms to Clinical Management

Neuro-oxidative-nitrosative stress in sepsis

Cerebral Perfusion in Sepsis

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