Cardiovascular and metabolic responses to catecholamine and sepsis prognosis: a ubiquitous phenomenon?

Many parameters have been associated with sepsis prognosis. In the present issue of Critical Care, Kumar and colleagues demonstrate that a preserved cardiac answer to dobutamine evaluated by radionucleotide measurements was associated with a better prognosis during septic shock. In this context, it is interesting to note that not only is the cardiac response to catecholamine stimulation associated with prognosis, but also the vascular and metabolic responses are associated. The ability of exogenous catecholamine to increase the arterial pressure (dopamine test) or to increase the lactate level is also related to prognosis. According to the ubiquitous character of catecholamine sensitivity, therefore, we should think in terms of cellular ability to respond to catecholamines in defining the concept of physiological reserve

Cardiovascular dysfunction in septic shock : Therapeutic improvement

La recherche sur le choc septique a connu en terme de translation clinique bien des échecs. L’analyse de ces échecs fait apparaître une prise en compte insuffisante de la complexité relationnelle entre les différents systèmes impliqués dans la défaillance cardiovasculaire. La prise en charge du choc septique fait l’objet de recommandations parmi lesquelles on retrouve l’importance de l’expansion volémique et l’utilisation de la Protéine C Activée. Ces deux thérapeutiques ont fait l’objet du présent travail de thèse. La première partie de ce travail est consacrée à l’expansion volémique en essayant d’en déterminer la meilleure modalité d’administration. Dans un modèle de choc endotoxinique chez le rat, nous avons montré que l’administration concomitante de noradrénaline et du remplissage vasculaire est associée à une baisse des volumes perfusés sans effet délétère sur l’hémodynamique systémique et régionale et sur la perfusion tissulaire. Dans un second temps nous nous sommes intéressés à l’impact de la PCa sur la dysfonction cardiovasculaire. L’administration de la PCa dans un modèle de choc endotoxinique améliore la pression artérielle, le débit cardiaque et la réactivité vasculaire/cardiaque à la norépinephrine et à la phénylephrine. Sur un plan mécanistique, la PCa diminue l’inflammation et le stress oxydant en diminuant l’expression des protéines et des métabolites impliqués. Ces effets cytoprotecteurs sont indépendants de son action anticoagulante. Afin de s’affranchir de l’interaction avec les éléments circulants du sang, ce travail a été complété ex vivo sur des artères isolées de souris après injection de LPS. En exposant in vitro ces artères à des concentrations thérapeutiques de PCa, nous avons démontré que la PCa améliore la contractilité et la relaxation en préservant la voie de la NOS endothéliale via Akt/PI3K, en produisant du métabolite COX2 vasorelaxant et en inhibant le facteur de transcription NF-kB. Pour conclure, ce travail permet de confirmer expérimentalement deux impressions cliniques : les vasopresseurs doivent être utilisés précocement et l’effet de la PCa est principalement hémodynamique par l’intermédiaire de sa voie cytoprotectrice, confirmant ainsi son indication préférentielle dans les états de choc.While quantitatively abundant, research on septic shock has, from a clinical perspective, encountered many setbacks. Analysis of these setbacks has underscored an overall insufficient consideration of the relational complexity between the various systems involved in cardiovascular failure. Conversely, the initial success observed with Activated Protein C is linked to actual fundamental research taking into account the interaction of two systems (inflammation and coagulation). Recent guidelines highlight the importance of vascular fluid loading and Activated Protein C (APC). The aim of the present work was to improve and to better understand these therapeutic strategies. In the first study, we aimed to assess hemodynamic, tissue oxygenation, and tissue perfusion changes by comparing traditional therapy (fluid resuscitation followed by vasopressor treatment) and alternative therapy (early vasopressor treatment) in a hyperkinetic and sedated model of endotoxic shock. The use of norepinephrine was associated with improved mean arterial pressure, sustained aortic and mesenteric blood flow, and better tissue oxygenation when compared with fluid resuscitation alone, irrespective of time of administration. The early use of norepinephrine plus volume expansion was associated with a higher proportion of blood flow redistributed to the mesenteric area, lower lactate levels, and less infused volume. Thus, the early use of norepinephrine is safe and may decrease the need for volume resuscitation. In the second study, we investigate the potential protective properties of therapeutic ranges of APC on a rat endotoxic shock model in terms of anti-inflammatory and cytoprotective pathways. APC partially prevented the reduction of blood pressure induced by LPS and improved both vascular hyporeactivity and myocardial performance. This was associated with a decreased upregulation of NF-?B, iNOS and MMP-9. LPS-induced tissue increases in NO and O2- production were decreased by APC. Moreover, APC decreased tissue leukocyte infiltration/activation. These data suggest that APC improves cardiovascular function i) by modulating the endotoxin induced-proinflammatory/prooxydant state, ii) by decreasing endothelial/leukocyte interaction and iii) by favoring stabilization of the extracellular matrix. In the third study, we examined the potential protective non anticoagulant effect of (ex-vivo) APC on vascular dysfunction induced by bacterial lipopolysaccharide (LPS) in mice arteries. LPS induced vascular dysfunction. After APC treatment, contractile capacity of aortas and endothelial responsiveness to vasorelaxant drug and shear stress were improved. We showed that rhAPC improved endothelial dysfunction in endotoxemia mice by increasing eNOS activation via Akt / PI3K pathway and NO-dependent dilation as well as COXs vasorelaxants metabolites. We noted that rhAPC also had an anti-inflammatory effect in the vascular wall by decreasing NF-kB activation. This result highlights important insights, regarding the mechanism underlying rhAPC induced-improvements microcirculation in septic shock. To conclude, our experimental results confirm and explain our clinical impression: vasopressor should be used early and APC has major hemodynamics effects through its cytoprotective pathway confirming its preferential use in severe cardiovascular dysfunction induced by sepsis

Dysfonction cardiovasculaire au cours du choc septique : Amélioration des stratégies thérapeutiques

While quantitatively abundant, research on septic shock has, from a clinical perspective, encountered many setbacks. Analysis of these setbacks has underscored an overall insufficient consideration of the relational complexity between the various systems involved in cardiovascular failure. Conversely, the initial success observed with Activated Protein C is linked to actual fundamental research taking into account the interaction of two systems (inflammation and coagulation). Recent guidelines highlight the importance of vascular fluid loading and Activated Protein C (APC). The aim of the present work was to improve and to better understand these therapeutic strategies. In the first study, we aimed to assess hemodynamic, tissue oxygenation, and tissue perfusion changes by comparing traditional therapy (fluid resuscitation followed by vasopressor treatment) and alternative therapy (early vasopressor treatment) in a hyperkinetic and sedated model of endotoxic shock. The use of norepinephrine was associated with improved mean arterial pressure, sustained aortic and mesenteric blood flow, and better tissue oxygenation when compared with fluid resuscitation alone, irrespective of time of administration. The early use of norepinephrine plus volume expansion was associated with a higher proportion of blood flow redistributed to the mesenteric area, lower lactate levels, and less infused volume. Thus, the early use of norepinephrine is safe and may decrease the need for volume resuscitation. In the second study, we investigate the potential protective properties of therapeutic ranges of APC on a rat endotoxic shock model in terms of anti-inflammatory and cytoprotective pathways. APC partially prevented the reduction of blood pressure induced by LPS and improved both vascular hyporeactivity and myocardial performance. This was associated with a decreased upregulation of NF-?B, iNOS and MMP-9. LPS-induced tissue increases in NO and O2- production were decreased by APC. Moreover, APC decreased tissue leukocyte infiltration/activation. These data suggest that APC improves cardiovascular function i) by modulating the endotoxin induced-proinflammatory/prooxydant state, ii) by decreasing endothelial/leukocyte interaction and iii) by favoring stabilization of the extracellular matrix. In the third study, we examined the potential protective non anticoagulant effect of (ex-vivo) APC on vascular dysfunction induced by bacterial lipopolysaccharide (LPS) in mice arteries. LPS induced vascular dysfunction. After APC treatment, contractile capacity of aortas and endothelial responsiveness to vasorelaxant drug and shear stress were improved. We showed that rhAPC improved endothelial dysfunction in endotoxemia mice by increasing eNOS activation via Akt / PI3K pathway and NO-dependent dilation as well as COXs vasorelaxants metabolites. We noted that rhAPC also had an anti-inflammatory effect in the vascular wall by decreasing NF-kB activation. This result highlights important insights, regarding the mechanism underlying rhAPC induced-improvements microcirculation in septic shock. To conclude, our experimental results confirm and explain our clinical impression: vasopressor should be used early and APC has major hemodynamics effects through its cytoprotective pathway confirming its preferential use in severe cardiovascular dysfunction induced by sepsis.La recherche sur le choc septique a connu en terme de translation clinique bien des échecs. L'analyse de ces échecs fait apparaître une prise en compte insuffisante de la complexité relationnelle entre les différents systèmes impliqués dans la défaillance cardiovasculaire. La prise en charge du choc septique fait l'objet de recommandations parmi lesquelles on retrouve l'importance de l'expansion volémique et l'utilisation de la Protéine C Activée. Ces deux thérapeutiques ont fait l'objet du présent travail de thèse. La première partie de ce travail est consacrée à l'expansion volémique en essayant d'en déterminer la meilleure modalité d'administration. Dans un modèle de choc endotoxinique chez le rat, nous avons montré que l'administration concomitante de noradrénaline et du remplissage vasculaire est associée à une baisse des volumes perfusés sans effet délétère sur l'hémodynamique systémique et régionale et sur la perfusion tissulaire. Dans un second temps nous nous sommes intéressés à l'impact de la PCa sur la dysfonction cardiovasculaire. L'administration de la PCa dans un modèle de choc endotoxinique améliore la pression artérielle, le débit cardiaque et la réactivité vasculaire/cardiaque à la norépinephrine et à la phénylephrine. Sur un plan mécanistique, la PCa diminue l'inflammation et le stress oxydant en diminuant l'expression des protéines et des métabolites impliqués. Ces effets cytoprotecteurs sont indépendants de son action anticoagulante. Afin de s'affranchir de l'interaction avec les éléments circulants du sang, ce travail a été complété ex vivo sur des artères isolées de souris après injection de LPS. En exposant in vitro ces artères à des concentrations thérapeutiques de PCa, nous avons démontré que la PCa améliore la contractilité et la relaxation en préservant la voie de la NOS endothéliale via Akt/PI3K, en produisant du métabolite COX2 vasorelaxant et en inhibant le facteur de transcription NF-kB. Pour conclure, ce travail permet de confirmer expérimentalement deux impressions cliniques : les vasopresseurs doivent être utilisés précocement et l'effet de la PCa est principalement hémodynamique par l'intermédiaire de sa voie cytoprotectrice, confirmant ainsi son indication préférentielle dans les états de choc

Dysfonction cardiovasculaire au cours du choc septique (Amélioration des stratégies thérapeutiques)

La recherche sur le choc septique a connu en terme de translation clinique bien des échecs. L analyse de ces échecs fait apparaître une prise en compte insuffisante de la complexité relationnelle entre les différents systèmes impliqués dans la défaillance cardiovasculaire. La prise en charge du choc septique fait l objet de recommandations parmi lesquelles on retrouve l importance de l expansion volémique et l utilisation de la Protéine C Activée. Ces deux thérapeutiques ont fait l objet du présent travail de thèse. La première partie de ce travail est consacrée à l expansion volémique en essayant d en déterminer la meilleure modalité d administration. Dans un modèle de choc endotoxinique chez le rat, nous avons montré que l administration concomitante de noradrénaline et du remplissage vasculaire est associée à une baisse des volumes perfusés sans effet délétère sur l hémodynamique systémique et régionale et sur la perfusion tissulaire. Dans un second temps nous nous sommes intéressés à l impact de la PCa sur la dysfonction cardiovasculaire. L administration de la PCa dans un modèle de choc endotoxinique améliore la pression artérielle, le débit cardiaque et la réactivité vasculaire/cardiaque à la norépinephrine et à la phénylephrine. Sur un plan mécanistique, la PCa diminue l inflammation et le stress oxydant en diminuant l expression des protéines et des métabolites impliqués. Ces effets cytoprotecteurs sont indépendants de son action anticoagulante. Afin de s affranchir de l interaction avec les éléments circulants du sang, ce travail a été complété ex vivo sur des artères isolées de souris après injection de LPS. En exposant in vitro ces artères à des concentrations thérapeutiques de PCa, nous avons démontré que la PCa améliore la contractilité et la relaxation en préservant la voie de la NOS endothéliale via Akt/PI3K, en produisant du métabolite COX2 vasorelaxant et en inhibant le facteur de transcription NF-kB. Pour conclure, ce travail permet de confirmer expérimentalement deux impressions cliniques : les vasopresseurs doivent être utilisés précocement et l effet de la PCa est principalement hémodynamique par l intermédiaire de sa voie cytoprotectrice, confirmant ainsi son indication préférentielle dans les états de choc.While quantitatively abundant, research on septic shock has, from a clinical perspective, encountered many setbacks. Analysis of these setbacks has underscored an overall insufficient consideration of the relational complexity between the various systems involved in cardiovascular failure. Conversely, the initial success observed with Activated Protein C is linked to actual fundamental research taking into account the interaction of two systems (inflammation and coagulation). Recent guidelines highlight the importance of vascular fluid loading and Activated Protein C (APC). The aim of the present work was to improve and to better understand these therapeutic strategies. In the first study, we aimed to assess hemodynamic, tissue oxygenation, and tissue perfusion changes by comparing traditional therapy (fluid resuscitation followed by vasopressor treatment) and alternative therapy (early vasopressor treatment) in a hyperkinetic and sedated model of endotoxic shock. The use of norepinephrine was associated with improved mean arterial pressure, sustained aortic and mesenteric blood flow, and better tissue oxygenation when compared with fluid resuscitation alone, irrespective of time of administration. The early use of norepinephrine plus volume expansion was associated with a higher proportion of blood flow redistributed to the mesenteric area, lower lactate levels, and less infused volume. Thus, the early use of norepinephrine is safe and may decrease the need for volume resuscitation. In the second study, we investigate the potential protective properties of therapeutic ranges of APC on a rat endotoxic shock model in terms of anti-inflammatory and cytoprotective pathways. APC partially prevented the reduction of blood pressure induced by LPS and improved both vascular hyporeactivity and myocardial performance. This was associated with a decreased upregulation of NF-?B, iNOS and MMP-9. LPS-induced tissue increases in NO and O2- production were decreased by APC. Moreover, APC decreased tissue leukocyte infiltration/activation. These data suggest that APC improves cardiovascular function i) by modulating the endotoxin induced-proinflammatory/prooxydant state, ii) by decreasing endothelial/leukocyte interaction and iii) by favoring stabilization of the extracellular matrix. In the third study, we examined the potential protective non anticoagulant effect of (ex-vivo) APC on vascular dysfunction induced by bacterial lipopolysaccharide (LPS) in mice arteries. LPS induced vascular dysfunction. After APC treatment, contractile capacity of aortas and endothelial responsiveness to vasorelaxant drug and shear stress were improved. We showed that rhAPC improved endothelial dysfunction in endotoxemia mice by increasing eNOS activation via Akt / PI3K pathway and NO-dependent dilation as well as COXs vasorelaxants metabolites. We noted that rhAPC also had an anti-inflammatory effect in the vascular wall by decreasing NF-kB activation. This result highlights important insights, regarding the mechanism underlying rhAPC induced-improvements microcirculation in septic shock. To conclude, our experimental results confirm and explain our clinical impression: vasopressor should be used early and APC has major hemodynamics effects through its cytoprotective pathway confirming its preferential use in severe cardiovascular dysfunction induced by sepsis.NANCY1-Bib. numérique (543959902) / SudocSudocFranceF

Vascular ATP-sensitive potassium channels are over-expressed and partially regulated by nitric oxide in experimental septic shock

International audiencePurpose To study the activation and expression of vascular (aorta and small mesenteric arteries) potassium channels during septic shock with or without modulation of the NO pathway. Methods Septic shock was induced in rats by peritonitis. Selective inhibitors of vascular KATP (PNU-37883A) or BKCa [iberiotoxin (IbTX)] channels were used to demonstrate their involvement in vascular hyporeactivity. Vascular response to phenylephrine was measured on aorta and small mesenteric arteries mounted on a wire myograph. Vascular expression of potassium channels was studied by PCR and Western blot, in the presence or absence of 1400W, an inducible NO synthase (iNOS) inhibitor. Aortic activation of the transcriptional factor nuclear factor-kappaB (NF-κB) was assessed by electrophoretic mobility shift assay. Results Arterial pressure as well as in vivo and ex vivo vascular reactivity were reduced by sepsis and improved by PNU-37883A but not by IbTX. Sepsis was associated with an up-regulation of mRNA and protein expression of vascular KATP channels, while expression of vascular BKCa channels remained unchanged. Selective iNOS inhibition blunted the sepsis-induced increase in aortic NO, decreased NF-κB activation, and down-regulated vascular KATP channel expression. Conclusions Vascular KATP but not BKCa channels are activated, over-expressed, and partially regulated by NO via NF-κB activation during septic shock. Their selective inhibition restores arterial pressure and vascular reactivity and decreases lactate concentration. The present data suggest that selective vascular KATP channel inhibitors offer potential therapeutic perspectives for septic shock.</p

Activated protein C improves LPS-induced cardiovascular dysfunction by decreasing tissular inflammation and oxidative stress.

International audienceBACKGROUND:: Recombinant human activated Protein C (APC) is used as an adjunctive therapeutic treatment in septic shock. APC seemingly acts on coagulation-inflammation interaction but also by decreasing proinflammatory gene activity, thus inhibiting subsequent production of proinflammatory cytokines, NO and NO-induced mediators, reactive oxygen species production and leukocyte-endothelium interaction. The hemodynamic effects of APC on arterial pressure and cardiac function are now well established in animal models. However, the specific effects of APC on heart and vessels have never been studied. OBJECTIVES:: To investigate the potential protective properties of therapeutic ranges of APC on a rat endotoxic shock model in terms of anti-inflammatory and cytoprotective pathways. DESIGN:: Laboratory investigation. SETTING:: University medical center research laboratory. INTERVENTIONS:: Rats were exposed to lipopolysaccharide (LPS) (10 mg/Kg iv.). Endotoxic shock was treated with infusion of saline with or without APC (33 mug/kg/h) during 4 hrs. Hemodynamic parameters were continuously assessed and measurements of muscle oxygen partial pressures, NO and superoxide anion (O2) by spin trapping, of NF-kappaB, metalloproteinase-9 (MMP-9) and inducible NO synthase (iNOS) by Western blotting, as well as leukocyte infiltration and MMP-9 activity were performed at both the heart and aorta level (tissue). MAIN RESULTS:: APC partially prevented the reduction of blood pressure induced by LPS and improved both vascular hyporeactivity and myocardial performance. This was associated with a decreased up-regulation of NF-kappaB, iNOS and MMP-9. LPS-induced tissue increases in NO and O2 production were decreased by APC. Furthermore, APC decreased tissue leukocyte infiltration/activation as assessed by a decrease in myeloperoxydase and matrix metalloproteinase 9 activity. CONCLUSIONS:: These data suggest that APC improves cardiovascular function i) by modulating the endotoxin induced-proinflammatory/prooxydant state, ii) by decreasing endothelial/leukocyte interaction and iii) by favoring stabilization of the extracellular matrix.</p

Combined Treatment with KV Channel Inhibitor 4-Aminopyridine and either γ-Cystathionine Lyase Inhibitor β-Cyanoalanine or Epinephrine Restores Blood Pressure, and Improves Survival in the Wistar Rat Model of Anaphylactic Shock

The mechanism of anaphylactic shock (AS) remains incompletely understood. The potassium channel blocker 4-aminopyridine (4-AP), the inhibitors of cystathionine γ-lyase (ICSE), dl-propargylglycine (DPG) or β-cyanoalanine (BCA), and the nitric oxide (NO) synthase produce vasoconstriction and could be an alternative for the treatment of AS. The aim of this study was to demonstrate the ability of L-NAME, ICSE alone or in combination with 4-AP to restore blood pressure (BP) and improve survival in ovalbumin (OVA) rats AS. Experimental groups included non-sensitized Wistar rats (n = 6); AS (n = 6); AS (n = 10 per group) treated i.v. with 4-AP (AS+4-AP), epinephrine (AS+EPI), AS+DPG, AS+BCA, or with L-NAME (AS+L-NAME); or AS treated with drug combinations 4-AP+DPG, 4-AP+BCA, 4-AP+L-NAME, or 4-AP+EPI. AS was induced by i.v. OVA (1 mg). Treatments were administered i.v. one minute after AS induction. Mean arterial BP (MAP), heart rate (HR), and survival were monitored for 60 min. Plasma levels of histamine, prostaglandin E2 (PGE2) and F2 (PGF2α), leukotriene B4 and C4, angiotensin II, vasopressin, oxidative stress markers, pH, HCO3, PaO2, PaCO2, and K+ were measured. OVA induced severe hypotension and all AS rats died. Moreover, 4-AP, 4-AP+EPI, or 4-AP+BCA normalized both MAP and HR and increased survival. All sensitized rats treated with 4-AP alone or with 4-AP+BCA survived. The time-integrated MAP “area under the curve” was significantly higher after combined 4-AP treatment with ICSE. Metabolic acidosis was not rescued and NO, ICSE, and Kv inhibitors differentially alter oxidative stress and plasma levels of anaphylactic mediators. The AS-induced reduction of serum angiotensin II levels was prevented by 4-AP treatment alone or in combination with other drugs. Further, 4-AP treatment combined with EPI or with BCA also increased serum PGF2α, whereas only the 4-AP+EPI combination increased serum LTB4. Serum vasopressin and angiotensin II levels were increased by 4-AP treatment alone or in combination with other drugs. Moreover, 4-AP alone and in combination with inhibition of cystathionine γ-lyase or EPI normalizes BP, increases serum vasoconstrictor levels, and improves survival in the Wistar rat model of AS. These findings suggest possible investigative treatment pathways for research into epinephrine-refractory anaphylactic shock in patients