Current Vascular Pharmacology - Volume 11, Issue 2, 2013

Sepsis is among the leading causes of death worldwide and its incidence is increasing. Defined as the host response to infection, sepsis is a clinical syndrome considered to be the expression of a dysregulated immune reaction induced by danger signals that may lead to organ failure and death. Remarkable progresses have been made in our understanding of the molecular basis of host defenses in recent years. The host defense response is initiated by innate immune sensors of danger signals designated under the collective name of pattern-recognition receptors. Members of the family of microbial sensors include the complement system, the Toll-like receptors, the nucleotide-binding oligomerization domainlike receptors, the RIG-I-like helicases and the C-type lectin receptors. Ligand-activated pattern-recognition receptors kick off a cascade of intracellular events resulting in the expression of co-stimulatory molecules and release of effector molecules playing a fundamental role in the initiation of the innate and adaptive immune responses. Fine tuning of proinflammatory and anti-inflammatory reactions is critical for keeping the innate immune response in check. Overwhelming or dysregulated responses induced by infectious stimuli may have dramatic consequences for the host as shown by the profound derangements observed in sepsis. Unfortunately, translational research approaches aimed at the development of therapies targeting newly identified innate immune pathways have not held their promises. Indeed, all recent clinical investigations of adjunctive anti-sepsis treatments had little, if any, impact on morbidity and all-cause mortality of sepsis. Dissecting the mechanisms underlying the transition from infection to sepsis is essential for solving the sepsis enigma. Important components of the puzzle have already been identified, but the hunt must go on in the laboratory and at the bedside.

In the late 19th century, it was already known that severe infections could be associated with cardiovascular collapse, a fact essentially attributed to cardiac failure. A major experimental work in the rabbit, published by Romberg and Pässler in 1899, shifted attention to disturbed peripheral vascular tone as the mechanism of hypotension in these conditions. In the first half of the 20th century, great progresses were made in the pathophysiologic understanding of hemorrhagic and traumatic shocks, while researchers devoted relatively little attention to septic shock. Progress in the hemodynamic understanding of septic shock resumed with the advent of critical care units. The hyperdynamic state was recognized in the late fifties and early sixties. The present short review ends with landmark studies by Max Harry Weil, demonstrating the importance of venous pooling, and John H. Siegel, which introduced the concept of deficient peripheral utilization of oxygen, inspiring later work on the microvascular disturbances of septic shock.

Purpose: To define some of the most common characteristics of vascular hyporesponsiveness to catecholamines during septic shock and outline current therapeutic approaches and future perspectives. Methods: Source data were obtained from a PubMed search of the medical literature with the following MeSH terms: Muscle, smooth, vascular/physiopathology; hypotension/etiology; shock/physiopathology; vasodilation/physiology; shock/therapy; vasoconstrictor agents. Results: NO and peroxynitrite are mainly responsible for vasoplegia and vascular hyporeactivity while COX 2 enzyme is responsible for the increase in PGI2, which also contributes to hyporeactivity. Moreover, K+ATP and BKCa channels are over-activated during septic shock and participate in hypotension. Finally, other mechanisms are involved in vascular hyporesponsiveness such as critical illness-related corticosteroid insufficiency, vasopressin depletion, dysfunction and desensitization of adrenoreceptors as well as inactivation of catecholamines by oxidation. Conclusion: In animal models, several therapeutic approaches, targeted on one particular compound have proven their efficacy in preventing or reversing vascular hyporesponsiveness to catecholamines. Unfortunately, none have been successfully tested in clinical trials. Nevertheless, very high doses of catecholamines (>5 μg/kg/min), hydrocortisone, terlipressin or vasopressin could represent an alternative for the treatment of refractory septic shock.

The endothelium takes part in the regulation of numerous physiological functions and lies at the interface of circulating blood and the vessel wall. Under physiological conditions, it is responsible for anticoagulant and anti-adhesive properties, and it regulates vasomotor tone and vascular homeostasis. Endothelial dysfunction has been associated with many pathophysiological processes, such as inflammation and oxidative and nitrosative stresses. Endothelial cells are precociously exposed to circulating signaling molecules and physical stresses, like in sepsis and septic shock. Septic shock is associated with hypotension and frequently with disseminated intravascular coagulation contributing to multiple organ failure and a high mortality rate. Impairment of endothelial function leads to phenotypic and physical changes of the endothelium, with deregulated release of potent vasodilators nitric oxide and prostacyclin, reduction of vascular reactivity to vasoconstrictors, associated with leukocytes' and platelets' aggregation, and increase in inducible nitric oxide synthase expression that can exert a negative feedback on endothelial nitric oxide synthase expression, with subsequent deregulation of nitric oxide signaling. Endothelial dysfunction therefore plays a major role in the pathophysiology of septic shock and organ dysfunction, and has been suggested to be a predictor of mortality in sepsis. Thus, early detection of endothelial dysfunction could be of great interest to adapt treatment in initial stage of sepsis. Current therapeutics used in sepsis mostly aim at controlling inflammation, vascular function and coagulation. Fluid administration, vasopressors, vasodilators and recombinant human activated protein C are also part of the treatments with the ultimate goal to exert beneficial effects on organ function and survival.

Microcirculatory dysfunction has been recently recognized as a key pathophysiologic process in the evolution of sepsis. In the present review, we discuss fundamental aspects of microcirculatory abnormalities during septic shock, including pathogenic mechanisms, technological assessment, clinical correlates and potential therapies. The most important function of the microcirculation is the regulation and distribution of flow within the different organs. In septic shock, microcirculatory dysfunction may arise as a result of several factors such as endothelial dysfunction, leukocyte-endothelium interactions, coagulation and inflammatory disorders, hemorheologic abnormalities, and functional shunting. Severity and persistence of these microcirculatory abnormalities are associated with bad prognosis and are not necessarily predicted by systemic variables. The introduction of bedside techniques that allow evaluation of the microcirculation into clinical practice has opened up a new field of functional hemodynamic monitoring. Recent data suggest that microcirculatory abnormalities can be staged in severity. Some microcirculatory indices are more accurately related to morbidity and mortality, and thus a definition of clinically relevant microcirculatory abnormalities is feasible. On the other hand, although several systemic variables do not predict microcirculatory status, high norepinephrine (NE) requirements and hyperlactatemia are associated with a much higher prevalence of relevant microcirculatory derangements. Therefore, severe septic shock patients could represent a more precise target for interventions, particularly in microcirculation-oriented clinical trials. Clinical research has identified various therapeutic approaches that are successful in modifying the microcirculation. Future research must determine whether some of these approaches are successful in improving outcome of critically ill patients by recruiting the microcirculation.

Brain dysfunction is a frequent complication of sepsis, usually defined as “sepsis-associated encephalopathy” (SAE). Its pathophysiology is complex and related to numerous processes and pathways, while the exact mechanisms producing neurological impairment in septic patients remain incompletely elucidated. Alterations of the cerebral blood flow (CBF) may represent a key component for the development of SAE. Reduction of CBF may be caused by cerebral vasoconstriction, either induced by inflammation or hypocapnia. Endothelial dysfunction associated with sepsis leads to impairment of microcirculation and cerebral metabolic uncoupling that may further reduce brain perfusion so that CBF becomes inadequate to satisfy brain cellular needs. The natural autoregulatory mechanisms that protect the brain from reduced/ inadequate CBF can be impaired in septic patients, especially in those with shock or delirium, and this further contributes to cerebral ischemia if blood pressure drops below critical thresholds. Sedative agents alter cerebro-vascular reactivity and may significantly reduce CBF. Although disorders of brain perfusion and alteration of CBF and cerebral autoregulation are frequently observed in humans with sepsis, their exact role in the pathogenesis of SAE remains unknown. Brain perfusion can further become inadequate due to cerebral microcirculatory dysfunction, as evidenced in the experimental setting. Microvascular alterations can be implicated in the development of electrophysiological abnormalities observed during sepsis and contribute to neurological alterations in septic animals. The aim of this review is to provide an update on the pathophysiology of brain perfusion in sepsis, with a particular focus on human clinical investigation and novel tools for CBF monitoring in septic patients.

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.

The intense systemic inflammatory response characterizing septic shock is associated with an increased generation of free radicals by multiple cell types in cardiovascular and non cardiovascular tissues. The oxygen-centered radical superoxide anion (O2 .-) rapidly reacts with the nitrogen-centered radical nitric oxide (NO.) to form the potent oxidant species peroxynitrite. Peroxynitrite oxidizes multiple targets molecules, either directly or via the secondary generation of highly reactive radicals, resulting in significant alterations in lipids, proteins and nucleic acids, with significant cytotoxic consequences. The formation of peroxynitrite is a key pathophysiological mechanism contributing to the cardiovascular collapse of septic shock, promoting vascular contractile failure, endothelial and myocardial dysfunction, and is also implicated in the occurrence of multiple organ dysfunction in this setting. The recent development of various porphyrin-based pharmacological compounds accelerating the degradation of peroxynitrite has allowed to specifically address these pathophysiological roles of peroxynitrite in experimental septic shock. Such agents, including 5,10,15,20-tetrakis(4- sulfonatophenyl)porphyrinato iron III chloride (FeTTPs), manganese tetrakis(4-N-methylpyridyl)porphyrin (MnTMPyP), Fe(III) tetrakis-2-(N-triethylene glycol monomethyl ether)pyridyl porphyrin) (FP-15) and WW-85, have been shown to improve the cardiovascular and multiple organ failure in small and large animal models of septic shock. Therefore, these findings support the development of peroxynitrite decomposition catalysts as potentially useful novel therapeutic agents to restore cardiovascular function in sepsis.

Various forms of circulatory shock (including septic shock) lead to an impairment of vascular function, which importantly contributes to the development of multiple organ failure and mortality. Such dysfunction of blood vessels consists of two principal components: vascular smooth muscle (VSM) dysfunction, and endothelial dysfunction. The VSM dysfunction (progressive, therapy-resistant loss of VSM responsiveness to vasoconstrictor catecholamines, such as noradrenaline) leads to a progressive deterioration of blood pressure in patients with circulatory shock. The endothelial dysfunction (loss of the ability of the endothelium to produce nitric oxide and other endothelium-derived factors) contributes to the impairment of microvascular blood flow, to the enhanced adhesion and activation of neutrophils and platelets, to coagulation problems, and perfusion/metabolism mismatch in the affected organs. Here we overview the vascular regulatory functions of the novel gasotransmitter hydrogen sulfide (H2S), with an emphasis on its potential role in the pathogenesis of vascular dysfunction in circulatory shock. We first review the roles of endogenously produced or exogenously administered H2S on vascular function. Next, we review the results of published studies using shock models induced by bacterial lipopolysaccharide, and by cecal ligation and puncture, a polymicrobial model of sepsis showing overproduction of H2S. Finally, we summarize the potential mechanisms by which H2S may contribute to vascular dysfunction in shock and show an example of how the vascular response to H2S is altered in a rat model of endotoxemia. In addition, we outline the potential means by which modulation of H2S (pharmacological inhibition of its biosynthesis or therapeutic donation) may affect the outcome in circulatory shock.

Cardiovascular failure in sepsis involves a combination of hypovolemia, decreased vascular tone, myocardial depression and microcirculatory alterations. Fluids represent the first line therapeutic intervention, with controversy regarding the type of fluid. Recent data indicate that albumin is safe and might even be beneficial in specific subgroups. Starches may be an alternative, although concerns exist on potential detrimental effects on renal function of old generation starches. Trials testing new generation starches are ongoing. When fluids fail to correct hypotension, vasopressor agents are used. Various adrenergic agents increase blood pressure, especially dopamine, noradrenaline and adrenaline, by stimulating alpha-adrenergic receptors. They also variably stimulate beta-adrenergic receptors, increasing cardiac contractility, heart rate, and splanchnic perfusion, but with increased risk of arrhythmias, immunomodulation and increased metabolism. Furthermore, dopamine stimulates dopaminergic receptors, resulting in doubtful effects on splanchnic and renal perfusion, but also in endocrine alterations. Do these pharmacologic differences among the various alpha-adrenergic agents translate into clinical differences? Several randomized trials tested the effects of these agents on outcome. Epinephrine produces more undesired effects than norepinephrine, but no clear cut differences on outcome were observed in underpowered trials. Norepinephrine should be preferred over dopamine, as suggested in one large trial and confirmed in a meta-analysis. Vasopressin may be considered as an alternative or in addition to adrenergic agents. In one large trial, no significant difference in outcome was observed, and the exact role of vasopressin still needs clarification. Finally, various inotropic agents can counteract septic myocardial depression. So far, no study supports their routine use, but these may be justified on an individual basis.

The primary goal in reopening an infarct-related artery is the restoration of myocardial tissue-level perfusion. In a variable proportion of patients with ST-elevation myocardial infarction, however, microcirculatory impairment may persist after epicardial coronary artery recanalization. This phenomenon is known as microvascular obstruction (MVO). Ischemic injury, reperfusion injury, and distal embolization along with the individual response to each of these mechanisms are variably involved in the pathogenesis of MVO in the single patient. Importantly, MVO is associated with a worse prognosis both at short- and long-term follow-up. MVO can be assessed in the cath-lab by simple angiographic indexes, such as Thrombolysis in Myocardial Infarction grade score and Myocardial Blush Grade, or by invasive measures of coronary flow pattern. Imaging techniques, such as myocardial contrast echocardiography or cardiac magnetic resonance, and ST-segment resolution on standard electrocardiogram are used in the days following reperfusion with the patient in the coronary care unit. In this article, we review the available data regarding pathogenesis, diagnosis and the prognostic significance of MVO after primary percurtaneous coronary intervention in ST-elevation myocardial infarction patients, with a brief highlighting on the crucial role of its prevention and its early detection.

Despite achievement of optimal epicardial coronary flow in the majority of patients treated for ST-segment elevation myocardial infarction (STEMI) by primary percutaneous coronary intervention (PPCI), myocardial no-reflow is a common phenomenon occurring in 5 to 50% of patients. The no-reflow phenomenon is a predictor of infarct size and an independent predictor of mortality both in the short and long term. Prevention of no-reflow is therefore a crucial step in improving prognosis of patients with STEMI. Several strategies including pharmacological and mechanical ones have been developed to improve microvascular perfusion in the setting of a myocardial infarction. Prevention starts by conservation of the microvascular reserve especially in patients at high risk of acute coronary syndromes such as diabetes patients. Optimal glycaemic control and the use of statins have been shown to reduce no-reflow in this context. Reducing ischaemic time by shortening door to balloon times, administration of intracoronary GP IIb/IIIa antagonists during PPCI and the use of manual aspiration thrombectomy have been shown to result in better myocardial perfusion and improved clinical outcome in major trials. In this review we discuss some of these major trials and studies of other therapeutic options that aim to prevent the no-reflow phenomenon.

No-reflow phenomenon is a consequence of percutaneous coronary intervention (PCI) which arises most of the time in the setting of myocardial infarction, but can be also the consequence of PCI in stable angina patients (rotatablator ablation technique or angioplasty in saphenous vein grafts). In this review, we summarize two ways of treating the noreflow according to the current literature. First through the pharmacological approach where several compounds have been assessed like adenosine, nitruprusside, verapamil, nicorandil, dipyridamole, epinephrine or cyclosporine. Second through the mechanical approach where few strategies have been examined like intra-aortic ballon pumping or postconditioning. Finally, we provide an algorithm for treating a no-reflow even though no studies showed a beneficial effect in terms of clinical endpoints.