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Inotropes et Vasopresseurs
- 1. Vasopresseurs & Inotropes 30/11/16 Diogo Sobreira Fernandes Marion Lebossé Groupement Hospitalier est Hôpital Cardiovasculaire et Pneumologique Louis Pradel Service d´Anesthesie Reanimation Pr. Jean Luc Fellahi
- 2. Plan 1.Médicaments Inotropes Positifs: Classification 2.Agonistes adrénergiques: Catécholamines et Non-catécholamines 3.Catécholamines endogènes 4.Catécholamines synthétiques 5.Non-catécholamines 6.Inhibiteurs de la Phosphodiestérase III 7.Sensibilisateurs Calciques 8.Vasopressine 9.Conclusion
- 3. 1. Médicaments Inotropes Positifs: Classification Fellahi JL, Fischer MO, Daccache JD, Gerard JL, Hanouz JL in Positive inotropic agents in myocardial ischemia-reperfusion injury: a benefit/risk analysis. Anesthesiology 2013 Jun;118(6):1460-5.
- 4. 1. Médicaments Inotropes Positifs: Classification Augmentation des niveau d'AMPc et [Ca2 +]i intracellulaire. Exception du Levosimendan. Fellahi JL, Fischer MO, Daccache JD, Gerard JL, Hanouz JL in Positive inotropic agents in myocardial ischemia-reperfusion injury: a benefit/risk analysis. Anesthesiology 2013 Jun;118(6):1460-5.
- 5. 2. Agonistes Adrenergiques: Catécholamines et Non-catécholamines Non-catécholamines: Phenyléphrine Midodrine Éphédrine Pseudoéphédrine Catécholamines: Fellahi JL, Fischer MO, Daccache JD, Gerard JL, Hanouz JL in Positive inotropic agents in myocardial ischemia-reperfusion injury: a benefit/risk analysis. Anesthesiology 2013 Jun;118(6):1460-5.
- 6. 2. Agonistes Adrenergiques: Catécholamines et Non-catécholamines Fellahi JL, Fischer MO, Daccache JD, Gerard JL, Hanouz JL in Positive inotropic agents in myocardial ischemia-reperfusion injury: a benefit/risk analysis. Anesthesiology 2013 Jun;118(6):1460-5.
- 7. 3. Catécholamines Endogène: Noradrénaline • effet α1 +++ Leone, M., F. Michel, and C. Martin. "Sympathomimétiques: pharmacologie et indications thérapeutiques en réanimation." thérapeutique 4 (2008): 7.
- 8. 3. Catécholamines Endogène: Noradrénaline Communal, Catherine, et al. "Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the β-adrenergic pathway." Circulation 98.13 (1998): 1329-1334.
- 9. 3. Catécholamines Endogène: Adrénaline Leone, M., F. Michel, and C. Martin. "Sympathomimétiques: pharmacologie et indications thérapeutiques en réanimation." thérapeutique 4 (2008): 7.
- 10. 5. Catécholamines Endogène: Adrénaline • 30 patients • IC > 3,51, PAM < 60 mmHg malgré RV + dopa 20µg/kg • NADN + Dobu vs ADN • Obtention PAM > 80 avec IC stable ou augmenté • Effet lactates, pHi gastrique
- 11. 5. Catécholamines Endogène: Adrénaline
- 12. 5. Catécholamines Endogène: Adrénaline • ADN ο Dobu + NAD
- 13. 3. Catécholamines Endogène: Dopamine • Effet dose dépendant : – D1-D2 : vasodilatation rénale, mésentérique, coronaire Leone, M., F. Michel, and C. Martin. "Sympathomimétiques: pharmacologie et indications thérapeutiques en réanimation." thérapeutique 4 (2008): 7.
- 14. 3. Catécholamines Endogène: Dopamine • Inconvénients : – Pro-arythmogène 1 • Dopamine dose “rénale” : OR 1,74 FA paroxystique post PAC – Favorise œdème cérébral 2 – Altération perfusion gastrique, du rapport Va/Q, de l’immunité cellulaire • Effet protecteur rénal ? 1 : Argalious, Maged, et al. "“Renal dose” dopamine is associated with the risk of new-onset atrial fibrillation after cardiac surgery." CCM 2005 2 : Beaumont A, Hayasaki K, Marmarou A, Barzo P, Fatouros P, Corwin F. Contrasting effects of dopamine therapy in experimental brain injury. J Neurotrauma 2001; 18: 1359-1372
- 15. 3. Catécholamines Endogène: Dopamine – > dopamine 2 µg/kg/min vs placebo Bellomo, R., et al. "Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. ANZICS Clinical Trials Group." Lancet 2000
- 16. 4. Catécholamines Synthétique: Dobutamine • Augmentation dose dépendante du débit cardiaque, principalement en fonction de l’augmentation de la fréquence cardiaque. • Balance besoins-apport O2 de la circulation coronaire. -> Syndrome de bas débit cardiaque avec RVS élévées -> Ne doit pas être utilísée seule en cas de RVS basses Gillies M et al in Bench-to-bedside review: Inotropic drug therapy after adult cardiac surgery – a systematic literature review. Critical Care 2005 Jun;9(3):266-79. Overgaard CB et al in Inotropes and Vasopressors: Review of Physiology and Clinical Use in Cardiovascular Disease. Circulation 2008 Sep 2;118(10):1047-56. Leone, M. et al in "Sympathomimétiques: pharmacologie et indications thérapeutiques en réanimation." thérapeutique 4 (2008): 7. Joseph L. Romson JL et al in Effects of Dobutamine on Hernodynamics and Left Ventricular Performance after Cardiopulmonary Bypass in Cardiac Surgical Patients. Anesthesiolohy 1990; 91: 13 18 -28
- 17. 4. Catécholamines Synthétique: Dobutamine -Catécholamine de 1ère ligne dans les centres de chir cardiaque français - Décision surtout fondée sur une diminution de la PAM Utilisation empirique associé a morbidité cardiaque post opératoire?
- 18. 4. Catécholamines Synthétique: Isoprénaline • L´activité inotrope + la plus puissante de toutes catécholamines. • Risque d’ischémie myocardique si utilisée seule (Tachycardie, inotropisme, hypotension et vol coronarien). • En association avec un alpha agoniste. Gillies M et al in Bench-to-bedside review: Inotropic drug therapy after adult cardiac surgery – a systematic literature review. Critical Care 2005 Jun;9(3):266-79. Leone, M. et al in "Sympathomimétiques: pharmacologie et indications thérapeutiques en réanimation." thérapeutique 4 (2008): 7.
- 19. 4. Catécholamines Synthétique: Isoprénaline • Les mécanismes de dépression cardiaque chez les patients atteints de choc septique ne sont pas liés à l'hypoperfusion myocardique ou à l'obstruction des vaisseaux coronariens. • Isoprénaline comme alternative à dobutamine?
- 20. 4. Catécholamines Synthétique: Isoprénaline Mérite d'être évalué, chez les patients avec choc septique sans antécédents connus de coronaropathie.
- 21. 5. Non-catécholamines: Phenyléphrine • Augmentation de la PAM / Augmentation de la postcharge sur le VG -> diminution du volume d'éjection. • Diminution de la capacitance veineuse / Augmentation de la précharge -> Augmentation du volume d'éjection. Gillies M et al in Bench-to-bedside review: Inotropic drug therapy after adult cardiac surgery – a systematic literature review. Critical Care 2005 Jun;9(3):266-79. Rebet O, Andremont O, Gerard JL, Fellahi JL, Hanouz JL et Fischer MO in Preload dependency determines the effects of phenylephrine on cardiac output in anaesthetised patients: A prospective observational study. Eur J Anaesthesiol 2016; 33:1–7 Le résultat hémodynamique (débit cardiaque), peut dépendre de la position du cœur dans la curve de Frank-Starling
- 24. 5. Non-catécholamines: Éphédrine • Inefficace si les stocks de NA sont épuisés (insufficiance cardiaque évoluée ou les états de choc prolongés. • Tachyphylaxie • Traitement temporaire d´une hypotension par baisse du débit cardiaque et des RVS (ALR ou surdosage en AG). Leone, M. et al in "Sympathomimétiques: pharmacologie et indications thérapeutiques en réanimation." thérapeutique 4 (2008): 7.
- 25. 5. Non-catécholamines: Éphédrine i) Effet de ces 2 agoniste adrénergique sur SctO2 ii) Identifier les variables physiologiques responsables par les changements de SctO2 induites par la phényléphrine et de l'éphédrine
- 27. 6. Inhibiteurs de Phosphodiestérase: Milrinone • Rationnel : – ↑AMPc – ↑contractilité, lusitrope + – Endépendant R-adrénergiques – Effet inodilatateur • IVG + RAS et P élevées • IVD + HTAP • Bas débit chez IC chonique ou BBloqué Overgaard, Christopher B., and Vladimír Džavík. "Inotropes and vasopressors review of physiology and clinical use in cardiovascular disease." Circulation 118.10 (2008): 1047-1056.
- 28. 7. Sensibilisateurs Calciques: Levosimendan • Calcium sensibilisateur – Sensibilisation troponine C • ↑ contractilité VG sans effet néfaste sur la diastole et sans ↑ consommation O2 – Ouverture canaux K+dpd • Vasodilatation arterio veineuse • Activité anti PDE3
- 29. 8. Sensibilisateurs Calciques: Levosimendan • LIDO study – Levosimendan vs Dobutamine – 200 Patients choc cardiogénique, FEVG <35% Follath, F., et al. "Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial." The Lancet 360.9328 (2002): 196-202.
- 30. 8. Vasopressine • HP ++, cœur • HypoTA, Hyperosmolarité • Action : – V1 : vasoconstriction, tonus vagal. ↓ production NO, désensbilisation adrénergique – V2 : ↑ réabsorption eau
- 31. 8. Vasopressine Patel, Bhavesh M., et al. "Beneficial effects of short-term vasopressin infusion during severe septic shock." The Journal of the American Society of Anesthesiologists 96.3 (2002): 576-582. • 23 patients choc S réfractaire : – 11 NAD, 12 Vasopressine
- 32. 9. Conclusions • Ionotrope idéal reste inconnu • E2 potentiellement graves • Pas de consensus • Comment choisir ? – État volémique du patient : précharge dpd ? – Quel mécanisme d’action ? – PK / PD, association pour diminuer les doses – Thérapeutiques associées : CPBIA, ECMO, Resynchronisation
Notes de l'éditeur
- The positive inotropic agents can be listed according to their cellular signaling pathways (fig. 1). We distinguish the catecholamines, the type III phosphodiesterase inhibitors (PDEIs III), the cardiac glycosides, and the calcium sensitizing agents (levosimendan). Cathecolamines - Beta 1 - Adrenergic receptor stimulation results in enhanced myocardial contractility through Ca2-mediated facilitation of the actin-myosin complex binding with troponin C and enhanced chronicity through Ca2 channel activation (Figure 1). Beta 2-Adrenergic receptor stimulation on vascular smooth muscle cells through a different intracellular mechanism results in increased Ca2 uptake by the sarcoplasmic reticulum and vasodilation (Figure 1). Alfa 1-adrenergic receptors on arterial vascular smooth muscle cells results in smooth muscle contraction and an increase in systemic vascular resistance. Cardiac glycosides Cardiac glycosides (digoxin) bind to the extracellular surface of the α subunit of myocardial Na-K-ATPase and inactivate this enzyme system. PDIs Phosphodiesterase 3 is an intracellular enzyme associated with the sarcoplasmic reticulum in cardiac myocytes and vascular smooth muscle that breaks down cAMP into AMP. PDIs lead to increased intracellular concentration of cAMP, which increases contractility in the myocardium and leads to vasodilation in vascular smooth muscle. Calcium Sensitizer It enhances myocardial contractility by binding to the cardiac troponin C with a high affinity and stabilizing the Ca2+-bound conformation of this regulatory protein. Levosimendan provides inotropic support without increasing intracellular Ca2+ concentrations which, in context with neutral effects on myocardial oxygen demand and heart rhythm, should be of benefit compared with catecholamines or PDEIs III. The main positive inotropic agents used in clinical practice induce a major increase in the intracellular cyclic adenosine monophosphate rate (either increasing the production for catecholamines, or decreasing the degradation for PDEIs III), which itself leads to a transitory increase in the [Ca2+]i responsible for the researched positive inotropic effect, but at the cost of a modification of the myocardial energy balance which speeds up in the end the cell death. Furthermore, increased concentrations of cyclic adenosine monophosphate and the subsequent changes in [Ca2+] i turnover are cardiotoxic and enhance electrophysiologic mechanisms that result in rhythm disturbances.17
- The positive inotropic agents can be listed according to their cellular signaling pathways (fig. 1). We distinguish the catecholamines, the type III phosphodiesterase inhibitors (PDEIs III), the cardiac glycosides, and the calcium sensitizing agents (levosimendan). Cathecolamines - Beta 1 - Adrenergic receptor stimulation results in enhanced myocardial contractility through Ca2-mediated facilitation of the actin-myosin complex binding with troponin C and enhanced chronicity through Ca2 channel activation (Figure 1). Beta 2-Adrenergic receptor stimulation on vascular smooth muscle cells through a different intracellular mechanism results in increased Ca2 uptake by the sarcoplasmic reticulum and vasodilation (Figure 1). Alfa 1-adrenergic receptors on arterial vascular smooth muscle cells results in smooth muscle contraction and an increase in systemic vascular resistance. Cardiac glycosides Cardiac glycosides (digoxin) bind to the extracellular surface of the α subunit of myocardial Na-K-ATPase and inactivate this enzyme system. PDIs Phosphodiesterase 3 is an intracellular enzyme associated with the sarcoplasmic reticulum in cardiac myocytes and vascular smooth muscle that breaks down cAMP into AMP. PDIs lead to increased intracellular concentration of cAMP, which increases contractility in the myocardium and leads to vasodilation in vascular smooth muscle. Calcium Sensitizer It enhances myocardial contractility by binding to the cardiac troponin C with a high affinity and stabilizing the Ca2+-bound conformation of this regulatory protein. Levosimendan provides inotropic support without increasing intracellular Ca2+ concentrations which, in context with neutral effects on myocardial oxygen demand and heart rhythm, should be of benefit compared with catecholamines or PDEIs III. The main positive inotropic agents used in clinical practice induce a major increase in the intracellular cyclic adenosine monophosphate rate (either increasing the production for catecholamines, or decreasing the degradation for PDEIs III), which itself leads to a transitory increase in the [Ca2+]i responsible for the researched positive inotropic effect, but at the cost of a modification of the myocardial energy balance which speeds up in the end the cell death. Furthermore, increased concentrations of cyclic adenosine monophosphate and the subsequent changes in [Ca2+] i turnover are cardiotoxic and enhance electrophysiologic mechanisms that result in rhythm disturbances.17
- 3 Classes of adrenergic agonists: Direct-acting: bind to and activate the receptors – cathecolamines and non-cathecolamines. Indirect-acting: Increase the concentration of norepinefrine at the neuroeffector junctions. Mixed-acting: direct and indirect actions.
- 3 Classes of adrenergic agonists: Direct-acting: bind to and activate the receptors – cathecolamines and non-cathecolamines. Indirect-acting: Increase the concentration of norepinefrine at the neuroeffector junctions. Mixed-acting: direct and indirect actions.
- ARVM = adult rat ventricular myocyte PRO = propanolol = B1 antago ; PZ = prazosin = A1 antago-&gt; Apoptose médiée par act B1 H89 = antago PKA PKA -&gt; active cnx Calcium -&gt; diltiazem : Ca bloqueur , diminue apoptose
- CABG : coronary artery bypass grafting
- Metabolized by COMT which makes it a good choice in patients with MAOI Because dobutamine directly stimulates β1 receptors, it does not rely on norepinephrine stores and may still be effective in catecholamine depleted states such as chronic CHF. However, in severe chronic CHF, the down-regulation of β-adrenergic receptors may hamper the drug’s effectiveness. Dobutamine may be useful in CHF and MI complicated by a low cardiac output state, although in cases of severe hypotension, it may not be effective because it lacks a significant α1-pressor effect. Prolonged treatment with dobutamine causes downregulation of β receptors; tolerance to its hemodynamic effects is significant after 3 days and may be temporarily offset by increasing the rate of infusion. Lower doses (5 g kg1 min1): Vascular smooth muscle binding results in combined 1-adrenergic agonism and antagonism, as well as 2-stimulation, such that the net vascular effect is often mild vasodilation, particularly at. Up to 15 g · kg1 · min1: increase cardiac contractility without greatly affecting periph-eral resistance, likely owing to the counterbalancing effects of 1-mediated vasoconstriction and 2-mediated vasodilation. Higher infusion rates: Vasoconstriction progressively dominates at. Dobutamine significantly increases myocardial oxygen consumption.
- L&apos;augmentation significative de la fréquence cardiaque est le mécanisme dominante de l&apos;augmentation du débit cardiaque avec dobutamine dans pacientes post-CPB. Hypotesis: An adverse postoperative outcome would occur more frequently when use of catecholamines is simply based on the clinical judgment of the cardiac anesthesiologists. Goal: The current prospective risk-adjusted observational study was therefore designed to estimate the influence of perioperative catecholamines administration on both major cardiac morbidity and mortality after elective adult cardiac surgery with CPB. The primary endpoint was major cardiac morbidity, defined as one of the following: (1) any postoperative sustained ventricular arrhythmia necessitating treatment, (2) the need for an intraaortic balloon pump in the ICU, or (3) postoperative myocardial infarction as defined above and previously. In conclusion, the perioperative use of dobutamine simply based on the clinical judgment of the attending anesthesiologists in low-risk patients undergoing elective cardiac surgery with CPB is associated with adverse postoperative cardiac outcome. A better assessment of the risk/benefit ratio of dobutamine administration is mandatory in cardiac surgery to avoid its inappropriate use and limit its potential deleterious effects.
- Its β1-adrenergic stimulation is significantly stronger than its β2 stimulation, but it still causes more β2-adrenergic activity than does dobutamine. The availability of superior pharmacologic options for most clinical indications has led to removal of isoproterenol from many hospital formularies. Because isoproterenol is not taken up into adrenergic nerve endings, its duration of action is slightly longer than that of the natural catecholamines. RV failure in Heart Transplantation: In order to optimize RV hemodynamics, one must consider the following manipulations. These include maximizing coronary perfusion through maintenance of aortic pressure, reducing preload to a distended and ischemic RV, decreasing RV afterload by reducing PVR, optimizing myocardial oxygen delivery and limiting ventricular oxygen consumption. As a pulmonary vasodilator, isoproterenol is one of the preferred inotropic agents in heart transplantation patients with elevated PVR.
- 1st study: However, because mechanisms for cardiac depression in septic shock patients are unrelated to myocardial hypoperfusion, or coronary vessels obstruction, isoproterenol is possibly an alternative to dobutamine for the treatment of sepsis-induced myocardial depression in septic shock patients. The present study showed that isoproterenol is effective to improve hemodynamics of septic shock patients, after fluid resuscitation and treatment with norepinephrine. Isoproterenol deserves to be reevaluated, at least in septic shock patients without known history of coronary artery disease.
- 1st study: However, because mechanisms for cardiac depression in septic shock patients are unrelated to myocardial hypoperfusion, or coronary vessels obstruction, isoproterenol is possibly an alternative to dobutamine for the treatment of sepsis-induced myocardial depression in septic shock patients. The present study showed that isoproterenol is effective to improve hemodynamics of septic shock patients, after fluid resuscitation and treatment with norepinephrine. Isoproterenol deserves to be reevaluated, at least in septic shock patients without known history of coronary artery disease.
- Altogether, these data suggest that anaesthesiologists should evaluate preload dependecy before phenylephrine administration because the effect on CI is strikingly different.
- Altogether, these data suggest that anaesthesiologists should evaluate preload dependecy before phenylephrine administration because the effect on CI is strikingly different.
- the aims of our study were to investigate the effect of phenylephrine and ephedrine bolus administration on cerebral oxygenation in anaesthetized patient to identify the physiological variables [MAP, CO,heart rate (HR), stroke volume (SV), end-tidal CO2 (EtCO2), oxygen saturation via pulse oximetry (SpO2 ), and bispectral index (BIS)] which are responsible for the changes in SctO2 induced by phenylephrine and ephedrine treatments. Exclusion criteria were symptomatic cardiovascular disease, poorly controlled hypertension (systolic arterial pressure ≥160 mm Hg), cerebrovascular disease, and poorly controlled diabetes mellitus (blood glucose ≥200 mg dl21). Anaesthesia-related hypotension (at least a 20% decrease in MAP or MAP,60 mm Hg) was treated with either phenylephrine or ephedrine. CO was monitored using an oesophageal Doppler (CardioQ, Deltex Medical, UK). COwas identified as the variable associated most significantly with SctO2 . The other variables (MAP, HR, SV, and EtCO2 ) which associated significantly with SctO2 became insignificant after taking CO into consideration. It should be noted that direct action of either phenylephrine or ephedrine on cerebral resistance vessels is practically nil since we know that vasoactive amines do not cross the blood–brain barrier. The distinctive effects of phenylephrine and ephedrine on SctO2 are thus explained by their distinctive impacts on CO.
- the aims of our study were to investigate the effect of phenylephrine and ephedrine bolus administration on cerebral oxygenation in anaesthetized patient to identify the physiological variables [MAP, CO,heart rate (HR), stroke volume (SV), end-tidal CO2 (EtCO2), oxygen saturation via pulse oximetry (SpO2 ), and bispectral index (BIS)] which are responsible for the changes in SctO2 induced by phenylephrine and ephedrine treatments. Exclusion criteria were symptomatic cardiovascular disease, poorly controlled hypertension (systolic arterial pressure ≥160 mm Hg), cerebrovascular disease, and poorly controlled diabetes mellitus (blood glucose ≥200 mg dl21). Anaesthesia-related hypotension (at least a 20% decrease in MAP or MAP,60 mm Hg) was treated with either phenylephrine or ephedrine. CO was monitored using an oesophageal Doppler (CardioQ, Deltex Medical, UK). COwas identified as the variable associated most significantly with SctO2 . The other variables (MAP, HR, SV, and EtCO2 ) which associated significantly with SctO2 became insignificant after taking CO into consideration. It should be noted that direct action of either phenylephrine or ephedrine on cerebral resistance vessels is practically nil since we know that vasoactive amines do not cross the blood–brain barrier. The distinctive effects of phenylephrine and ephedrine on SctO2 are thus explained by their distinctive impacts on CO.
- Ne passe pas par R beta donc efficace chez IC chronique, si Bbloquants effet inotrope positif, effet vasodilatateur sur les vaisseaux de résistance (artères systémiques et pulmonaires) et de capacitance (grandes veines centrales). Attention hypovolémie
- En france, terlipressine. ADH Action préservée si acidose, hypoxie contrairement catécholamines
- Inotrope ideal : on /off, pas d’augm conso O2, pas de tachyphylaxie, inotropisme B-indpd, non arrythmogène, pas d’augmentation Ca intra