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Inotropes and vasopressors in cardiogenic shock

UPDATE INOTROPES and VASOPRESSOR IN CARDIOGENIC SHOCK

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Inotropes and vasopressors in cardiogenic shock

  1. 1. INOTROPES aNdINOTROPES aNd vaSOPRESSORS INvaSOPRESSORS IN caRdIOgENIc ShOckcaRdIOgENIc ShOck Dr. Anwar Yusr Critical Care Consultant University of Science and Technology Hospital - Sana'a USTH
  2. 2. Cardiogenic Shock • Cardiogenic shock is defined as: – SBP <90 mmHg for at least 30 minutes. – which is secondary to myocardial dysfunction. –Cardiac index (CI) < 2.2 l/min/m2. – PCWP > 18 mmHg. • It is associated with signs of tissue hypoperfusion:- – decreased urine output: < 0.5ml/kg/hr. – altered mental status: Confusion. – peripheral vasoconstriction – sweaty, cold, pale. – Capillary filling time >2 sec.
  3. 3. PATIENT WITH AHF Bedside assessment to identify haemodynamic profile CONGESTION? YES (95% of AHF patients) NO (5% of AHF patients) “Wet” “Dry” POOR PERFUSION? NO “Wet” & “Warm” NO “Dry” & “Warm” YES “Dry” & “Cold” YES “Wet” & “Cold” Adapted from 2016 ESC HF Guildeines
  4. 4. “Wet” & “Cold” Systolic blood pressure < 90 mmHg? YES NO  Inotropic agent.  Consider vasopressor in refractory cases.  Diuretic (when perfusion corrected).  Consider mechanical circulatory support if no response to drugs.  Vasodilators.  Diuretics.  Consider inotropic agent in refractory cases. Adapted from 2016 ESC HF Guildeines
  5. 5. Therapeutic Targets • Inotrope support is indicated when there is evidence of tissue hypoperfusion despite fluid optimisation. • Generally recommended therapeutic targets of haemodynamic parameters are: 1. MAP 65-75 mmHg. 2. CI > 2.5 [l/min/m2]. 3. SVR 800-1000 (dyne/s/m-5). 4. SVO2 > 65%. 5. CPI > 0.6 [w/m2). (MAP x cardiac index x 0.0022). • All of which aim to improve organ perfusion with the minimized use of vasoactive drugs and heart rate <110 bpm.
  6. 6. Simplified schematic of postulated intracellular actions of beta -adrenergic agonists
  7. 7. Dobutamine • β1 >>>β2>>α1 (β1: β2 = 3:1). • Inotropic (increase CO), Mild Chronotropic and vasodilation: < 5micg/kg/min. (At higher doses >15, peripheral effect becomes vasoconstriction).  Should be avoided if SBP < 80 mmHg.  Worsening ischemia due to (increase O2 consumption).  ? Loss of efficacy in patients on chronic beta blocker therapy/acidosis/hypoxia. AF, Ventricular arrhythmias (rare).  Tolerance after 48h. CONTRAINDICATION : Hypotension and HOCM.
  8. 8. DOPAMINE <3 mcg 3 - 10 mcg > 10 mcg ↑Contractility Minimal change in HR and SVR ↑ Renal BF ↑ Splanchnic BF Modest ↑ CO ↑ Renal BF ↓Proximal Tub. Na Absorbtion ↑ Splanchnic BF ↑ HR, Vasoconstriction ↑/ ↓ Renal BF ↓/↑ Splanchnic BF  Dose Dependent effect of Dopamine. D > β1> α1>> β2. Tachycardia, Tachyarrythmias, and Worsening ischemia.
  9. 9. NOREPINEPHRINE α1>>β1> β2  Powerful vasopressor, modest inotropic effects, Less chronotropic.  Predominantly a vasoconstrictor and a weak inotrope. As a vasopressor: 100-fold more potent than dopamine. 3 to 5 times more potent than phenylephrine for raising MAP.  Cardiotoxic at high doses due to apoptosis in experimental models. ( PKA mediated).
  10. 10. SOAP II trial Norepinephrine is preferred over dopamine when blood pressure is low. (IIB/B) Medical support with inotropes and vasopressor agents should be individualized and guided by invasive hemodynamic monitoring. Use of dopamine in this setting may be associated with excess hazard. De Backer et al. NEJM 2010;369:779-789 2012 ESC Guidelines for the management of acute myocardial infarction in patients presenting with STEMI Comparison of norepinephrine and dopamine in the treatment of shock (SOAP-II trial)
  11. 11. EPINEPHRINE α1 predominantly Vasoconstriction ↓ Renal BF. ↓ Splanchnic BF. ↑ Glucose. β1 predominantly ↑HR. ↓ Duration of Systole. ↑ Myocardial contract Periph. arteriolar dilt. ↑/ ↓ Renal BF. ↑ Renin secretion. ↑/ ↓ Splanchnic BF. ↑ Glucose. Hypokalemia. Epinephrine Low Dose (< 0.05-0.1 mcg/kg/min) High Dose (> 0.1 μg/kg/min)
  12. 12. Adrenaline Independent Predictor of Survival curves for use of adrenaline Mortality Propensity score: age, gender, medical history (myocardial infarction, coronary artery bypass graft surgery, hypertension, renal insufficiency), acute coronary syndrome as the etiology of cardiogenic shock, resuscitation prior to inclusion and initial presentation (confusion, blood lactate, creatinine, systolic blood pressure, sinus rhythm, and left ventricular ejection fraction). Tarvasmaki T et al. Crit Care Med 2016;20:208
  13. 13. Adrenaline Use Related to Deterioration in Cardiac and Renal Biomarkers in CS Tarvasmaki T et al. Crit Care Med 2016;20:208 Adrenaline use associated with markedly worse evolution of cardiac and renal biomarker levels over the initial 96 hours; likely due to an increase in myocardial oxygen consumption, excessive vasoconstriction and/or direct organ toxic damage due to intense adrenergic stimulation.
  14. 14. Epinephrine vs Norepinephrine in AMI Related CS Levy B. et al. J Am Coll Cardiol. 2018;72(2):173–82 similar effects on arterial pressure and cardiac index but a higher incidence of refractory shock with epinephrine.
  15. 15. Phosphodiesterase inhibitor • Bypiridine: Amrinone. Milrinone. • Imidazole  Enoximone.  Piroximone.
  16. 16. PDIs - MILRINONE  Vasodilation > positive inotropy..  Inotropic, Chronotropic, Lusitropic. Systemic circulation effects: - Vasodilation. - Increased organ perfusion. - Decreased SVR. - Decreased arterial pressure. Cardiopulmonary effects: - Increased contractility and heart rate. - Increased stroke volume and EF. - Decreased ventricular preload. - Decreased PCWP.
  17. 17. Milrinone Minimal ↑ in O2 demand ↓ SVR ↓ PVR Minimal ↑ HR ↑ CO Diastolic Relaxation
  18. 18. Milrinone- Clinical application The main use is in reducing RV afterload and in advanced non-ischaemic cardiomyopathies.  Theoretical advantages compared to β agonists : - Chronotropic effect is less than β agonists. - Less tachycardia for AF patients. - Better efficacy for those on chronic BB therapy. - Lusitropic and vasodilatory effects (esp. pulmonary).  Loading dose: 50 mcg/kg administered over 10 minutes followed by 0.375 mcg/kg/minute. (However more expensive, hypotension and prolonged action).
  19. 19. CALCIUM SENSETIZING AGENTS
  20. 20. Pollesello P, Papp Z. J Cardiovasc Pharmacol 2007;50:257-63 Molecular targets, mechanisms of action and pharmacological effects of levosimendan Molecular targets Mechanisms of action Pharmacological effects Therapeutic effects Selective binding to the calcium- saturated form of cardiac troponin C Calcium sensitization of contractile proteins Positive inotropy Increased ejection fraction Anti-stunning Opening of KATP channels on smooth muscle cells in vasculature Membrane hyper- polarization. Vasodilation in all vascular beds (also coronary and peripheral circulation). Lower pre- and afterload Anti-ischaemic Tissue perfusion. Opening of KATP mitochandria channels in cardiomyocytes Protection of mitochondria in ischaemia-reperfusion Pre-conditioning Anti- apoptotic Cardioprotection Anti- ischaemic Long-term benefits
  21. 21. Levosimendan - Pharmacology • Loading :Loading : 12-24µg/kg over 10 min.12-24µg/kg over 10 min. • Infusion:Infusion: 0.05-0.2µg/kg/min.0.05-0.2µg/kg/min. • Active metabolite – OR-1896 (half life of 80 hours) – responsible for prolonged action upto several days after stopping infusion. Side effects • Hypotension 4%–10% of patients, depending on the dose and use of a bolus. • Headache. • Arrhythmias: ventricular extra-systoles, and sinus tachycardia, occurred mainly or exclusively at higher doses.
  22. 22. LEVOSIMENDAN - Evidence • Significant mortality benefit for critically ill patients with heart failure and patients undergoing cardiac surgery. (Metanalysis from 11 controlled trials (2009) • Improves mortality after coronary revascularisation compared to standard therapy. (Critical Care 2011) Only intravenous positive inotrope that has had a mortality benefit consistently. Uniform physiological benefits for coronary, renal and G.I systems. “ALL THESE DATA SUPPORT THE USE OF LEVOSIMENDAN IN POST MI CARDIOGENIC SHOCK PATIENTS FOR ITS CALCIUM SENSITIZING , INOTROPIC AND ANTI MYOCARDIAL STUNNING PROPERTIES”
  23. 23. COMPARISON BETWEEN LEVOSIMENDAN, MILRINONE AND DOBUTAMINE Feature Levosimendan Milrinone Dobutamine Class Calcium channel Phosphodiesterase-III Catecholamine(β- sensitizer inhibitor adrenergic agent) ↑intracellular Ca No Yes Yes concentrations Vasodilator Coronary and Peripheral Mild peripheral systemic ↑Myocardial O₂ No No Yes demand Arrhythmogenic Rare and may be due potential Ventricular and Ventricular ectopic to QTc prolongation supraventricular activity; less arrhythmias arrhythmogenic than milrinone Adverse events Headache, Ventricular Tachycardia and hypotension irregularities, increased SBP on hypotension, headache overdosage
  24. 24. Risks of Inotropes and Vasopressors in CS Van Diepen S. J Am Coll Cardiol. 2018;72(2):183
  25. 25. What Do The ESC Guidelines 2016 Say? Recommendations for inotropic agents and vasopressors in patients with cardiogenic shock Short-term, i.v. infusion of inotropic agents may be considered in patients with hypotension (SBP <90 mmHg) and/or signs/symptoms of hypoperfusion despite adequate filling status, to increase cardiac output, increase blood pressure, improve peripheral perfusion and maintain end-organ function. IIb C An intravenous infusion of levosimendan or a PDE III inhibitor may be considered to reverse the effect of beta- blockade if beta-blockade is thought to be contributing to hypotension with subsequent hypoperfusion. IIb C Inotropic agents are not recommended unless the patient is symptomatically hypotensive or hypoperfused because of safety concern. III A 556, 557
  26. 26. What Do The ESC Guidelines Say? Recommendations for inotropic agents and vasopressors in patients with cardiogenic shock A vasopressor (norepinephrine preferably) may be considered in patients who have cardiogenic shock, despite treatment with another inotrope, to increase blood pressure and vital organ perfusion. IIb B 558 It is recommended to monitor ECG and blood pressure when using inotropic agents and vasopressors, as they can cause arrhythmia, myocardial ischaemia, and in the case of levosimendan and PDE III inhibitors also hypotension. I C 540, 559 -563 In such cases intra-arterial blood pressure measurement may be considered. IIb? C
  27. 27. 31 Emergency Management of Complicated STEMIEmergency Management of Complicated STEMI Administer • Fluids • Blood transfusions • Cause-specific interventions Consider vasopressors Arrhythmia Bradycardia Tachycardia Systolic BP Greater than 100 mm Hg Systolic BP 70 to 100 mm Hg NO signs/symptoms of shock Systolic BP 70 to 100 mm Hg Signs/symptoms of shock Systolic BP less than 70 mm Hg Signs/symptoms of shock Dobutamine 2 to 20 mcg/kg per minute IV Low Output - Cardiogenic Shock Nitroglycerin 10 to 20 mcg/min IV Dopamine 5 to 15 mcg/kg per minute IV Norepinephrine 0.5 to 30 mcg/min IV Hypovolemia Administer • Furosemide IV 0.5 to 1.0 mg/kg • Morphine IV 2 to 4 mg • Oxygen/intubation as needed • Nitroglycerin SL, then 10 to 20 mcg/min IV if SBP greater than 100 mm Hg • Dopamine 5 to 15 mcg/kg per minute IV if SBP 70 to 100 mm Hg and signs/symptoms of shock present • Dobutamine 2 to 20 mcg/kg per minute IV if SBP 70 to 100 mm Hg and no signs/symptoms of shock FirstlineofactionSecondlineofactionThirdlineofaction See Section 7.7 in the ACC/AHA Guidelines for Patients With ST-Elevation Myocardial Infarction Check Blood Pressure Clinical signs: Shock, hypoperfusion, congestive heart failure, acute pulmonary edema Most likely major underlying disturbance? Further diagnostic/therapeutic considerations (should be considered in nonhypovolemic shock) Diagnostic Therapeutic ♥ Pulmonary artery catheter ♥ Intra-aortic balloon pump ♥ Echocardiography ♥ Reperfusion/revascularization ♥ Angiography for MI/ischemia ♥ Additional diagnostic studies Acute Pulmonary Edema Check Blood Pressure Systolic BP Greater than 100 mm Hg and not less than 30 mm Hg below baseline ACE Inhibitors Short-acting agent such as captopril (1 to 6.25 mg) Circulation 2000;102(suppl I):I-172-I-216.
  28. 28. 32Antmen, JACC, 2004;44:671
  29. 29. Inotropes and Vasopressors ACC/AHAGuidelines BP <70:-  Norepinephrine (0.5-30 micg/min) Switch to Dopamine (5-15 micg/kg/min) once SBP ≥80  SBP 70-100  Dopamine (5-15 micg/kg/min) Add dobutamine (2-20 micg/kg/min) once SBP ≥90. • Refractory hypotension + shock: → Amrinone or milrinone may improve cardiac output. → Levosimendan may be preferable if patient on chronic BB.
  30. 30. Newer Inotropic Agents • Cardiac myosin activators- Omecamtive mecarbil. • Na/K-ATPase inhibitors- Istaroxime. • Ryanodine receptor stabilizers JTV-519(K201), S107, S44121 • SERCA2a activators- MYDICAR
  31. 31. Inotropic mechanisms and drugs (Hasenfuss & Teerlink, EHJ 2011) Inotropic mechanism Drugs Comments (MSN) Sodium-Potassium ATPase inh. Digoxin Mild inotrope, diastolic dysfunction, vagal, arrythmias B-adrenoreceptor stimulation Dobutamine, Dopamine HR increase, arrythmias A and B adrenoreceptor stimulation Adrenaline, Noradrenaline Vasoconstriction, HR and arrythmias PDE inhibition Enoximone, milrinone HR inc, Vasodilatation, some inotropic effect, arrythmias Calcium sensitation Levosimendan Mild inotrope, calcium sensitisation, impr. mitochonrial function, vasodilatation, HR may increase, hypotension related to arrythmias Acto-myosin cross-bridge activation Omecamtiv mecarpil Prolongs contractile phase, further evidence needed SERCA activation Gene transfer Applied in chronic HF SERCA activation + vasodilatation Nitroxyl donor, CLX- 1020 No study results posted at clinicaltrials.cov Ryanodine receptor stabilization S44121 No studies registered Sodium-potassium cross- bridge activation + SERCA activation Istaroxime Istaroxime decreases PCWP, increases SBP, and decreases diastolic stiffness in patients with acute heart failure syndrome. Program ongoing, some study withdrawals Energetic modulation Etoximir, pyruvate No studies registered
  32. 32. New inotropic agents Hasenfuss, et al. Eur Heart J 2011;32:1838- 1845 Istaroxime: Inotropic effect ∼inhibition of Na-K ATPase Lusitropic effect ∼stimulation of SERCA 2a. •↑ systolic blood pressure. •↓ heart rate. Myosin activators (e.g. Omecamtiv mecarbil): •↑ rate of effective myosin cross-bridge formation. → ↑ duration of myocyte contraction. •No effect on cAMP or calcium.
  33. 33. OMECANTIV MECARBIL Cardiac Specific Myosin Activator. •Stimulate myosin-ATPase Accelerates the rate of actin- dependent phosphate release from the actin-myosin crossbridge Promotes transition to the force producing on-state of the cross bridge More cross-bridges activated per unit time Increased contractile force
  34. 34. Omecamtiv Mecarbil [cardiac myosin activators] Cleland JG, Teerlink JR, Senior R, et al. The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: A double-blind, placebo- controlled, crossover, dose-ranging phase 2 trial. Lancet 2011 •Double blind, placebo controlled, dose ranging trial •Infusions: 2 vs. 24 vs. 72 hr •Plasma drug concentration measured at the end of each infusion •Safety and tolerability assessed •45 patients 38 Noveltherapies Plasma concentration dependent effects ↑ ventricular ejection time with no change in dp/dt Small ↓ in heart rate Reduction in end-systolic and end-diastolic volumes ↑ cardiac ischemia ATOMIC-AHF trial underway
  35. 35. 70% 60% 50% 40% 30% 20% 10% 0% Tilarginine 48% 42% Placebo Tilarginine: Placebo RR: 1.14 95% CI: 0.92-1.41 P=0.24 0 5 10 15 20 25 30 Days from randomization JAMA. 2007;297(15):1657-1666. 30day-Mortality Effect of Tilarginine Acetate in Patients With Acute Myocardial Infarction and Cardiogenic Shock The TRIUMPH Randomized Controlled Trial
  36. 36. Cyclosporine Cyclosporine is another new drug which has been proposed for reduction of re-perfusion injury in cases of large size AMI complicated with CS. The CLOTILDE trial (Cyclosporine in Acute Myocardial Infarction Complicated by Cardiogenic Shock, NCT01901471), tested the hypothesis that administration of cyclosporine during the reperfusion phase of AMI would reduce the infarct size by 20-40%, reduce the risk of multi- organ failure and improve the clinical status of these patients.
  37. 37. GLUCAGON • Increases cardiac output by approximately 20%, which is associated with a decrease in peripheral vascular resistance with less myocardial oxygen demand when compared with norepinephrine. • Administer this agent to patients with cardiogenic shock who do not respond to conventional therapy or cannot tolerate other agents because of the development of significant arrhythmias or hematologic toxicity.
  38. 38. GENE THERAPY • To increase sarcoplasmic reticulum calcium pump activity by stimulating the calcium pumps. • Most approaches are related to reduced SR calcium uptake, however, abnormal SR leak has also been considered. • It has been shown in isolated myocytes that overexpression of the RyR-regulatory protein FKBP12.6 increases SR calcium content and fractional shortening.
  39. 39. Summary  Treatment of cardiogenic shock relies mainly on Revasuclarization and mechanical support.  INOTROPES INDICATED Only if symptoms and signs of congestion and hypoperfusion are present.  INOTROPES May be useful as initial therapy bridging to MCS + definitive therapy (Revasc, LVAD, transplant).  Inotropes and pressors are associated with either no benefit or worse outcomes.  Use the lowest dose able to achieve desired targets (resolution of hypoperfusion and end organ damage) and for the shortest possible time.  No RCT demonstrating clear clinical benefit for any drug, Inotrope of choice based on local expertise.
  40. 40. Summary  In spite of this, virtually all cardiogenic shock patients receive treatment with catecholamines usually a combination of inotrope and vasopressor.  Accumulating evidence favors norepinephrine over dopamine.  Adrenaline (and dopamine) use seem to be associated with increased mortality.  PDE III inhibitors or levosimendan should be favoured in patients on beta-blockers and levosimendan in patients with decompensated chronic heart failure or for postoperative cardiac stunning.  Positive long-term effects of levosimendan on mortality are still controversial.
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UPDATE INOTROPES and VASOPRESSOR IN CARDIOGENIC SHOCK

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