INOTROPES IN CARDIOGENIC SHOCK

1. USTH INOTROPES and vasopressors in cardiogenic shock Dr. Anwar Yusr Critical Care Consultant University of Science and Technology Hospital - Sana'a

2. Cardiogenic Shock • Cardiogenic shock is defined as: • SBP <90 mmHgfor 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. 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” YES “Dry” & “Cold” NO “Dry” & “Warm” YES “Wet” & “Cold” Adapted from 2016 ESC HF Guildeines

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. Therapeutic Targets • Inotrope support is indicated when there is evidence of tissuehypoperfusion despite fluid optimisation. • Generally recommended  therapeutic targets of haemodynamic parameters are: • MAP 65-75 mmHg. • CI> 2.5  [l/min/m2]. • SVR800-1000 (dyne/s/m-5). • SVO2> 65%. • 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.

7. Simplified schematic of postulated intracellular actions of beta -adrenergic agonists

8. Dobutamine • β1 >>>β2>>α1 (β1: β2 = 3:1). • Inotropic (increase CO), Mild Chronotropicand 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 after48h. • CONTRAINDICATION : Hypotension and HOCM.

9. DOPAMINE • D > β1> α1>> β2. • Dose Dependent effect of Dopamine. 3 - 10 mcg > 10 mcg <3 mcg ↑ HR, Modest ↑ CO ↑Contractility Vasoconstriction ↑ Renal BF Minimal change in HR and SVR ↑/ ↓ Renal BF ↓Proximal Tub. Na Absorbtion ↑ Renal BF ↓/↑ Splanchnic BF ↑ Splanchnic BF ↑ Splanchnic BF • Tachycardia, Tachyarrythmias, and Worsening ischemia.

10. NOREPINEPHRINE • α1>>β1> β2 • Powerfulvasopressor, 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).

11. Comparison of norepinephrine and dopamine in the treatment of shock (SOAP-II trial) SOAP IItrial 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 withSTEMI 2013 ACCF/AHA Guideline for the Management of ST-Elevation MyocardialInfarction

12. EPINEPHRINE Epinephrine Low Dose (< 0.05-0.1 mcg/kg/min) High Dose (> 0.1 μg/kg/min) β1 predominantly ↑HR. ↓ Duration of Systole. ↑ Myocardial contract Periph. arteriolar dilt. ↑/ ↓ Renal BF. ↑ Renin secretion. ↑/ ↓ Splanchnic BF. ↑ Glucose. Hypokalemia. α1 predominantly Vasoconstriction ↓ Renal BF. ↓ Splanchnic BF. ↑ Glucose.

13. 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

14. Adrenaline Use Related to Deterioration in Cardiac and Renal Biomarkers in CS 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. Tarvasmaki T et al. Crit Care Med2016;20:208

15. Epinephrine vs Norepinephrine in AMI Related CS similar effects on arterial pressure and cardiac index but a higher incidence of refractory shock with epinephrine. Levy B. et al. J Am Coll Cardiol. 2018;72(2):173–82

16. Phosphodiesterase inhibitor • Bypiridine: • Amrinone. • Milrinone. • Imidazole • Enoximone. • Piroximone.

17. 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.

18. Milrinone Minimal ↑ HR ↑ CO Diastolic Relaxation Minimal ↑ in O2 demand ↓ SVR ↓ PVR

19. 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 βagonists. • Less tachycardia for AF patients. • Better efficacy for those on chronic BB therapy. • Lusitropic and vasodilatoryeffects(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).

20. CALCIUM SENSETIZING AGENTS

22. Molecular targets, mechanisms of action and pharmacological effects of levosimendan Pollesello P, Papp Z. J Cardiovasc Pharmacol 2007;50:257-63

23. Levosimendan- Pharmacology • Loading : 12-24µg/kg over 10 min. • Infusion: 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 • Hypotension4%–10% of patients, depending on the dose and use of abolus. • Headache. • Arrhythmias:ventricular extra-systoles, and sinus tachycardia, occurred mainly or exclusively at higherdoses.

25. 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 revascularisationcompared to standard therapy. (Critical Care 2011) “ALL THESE DATA SUPPORT THE USE OF LEVOSIMENDAN INPOST MI CARDIOGENIC SHOCK PATIENTS FOR ITS CALCIUM SENSITIZING , INOTROPIC AND ANTI MYOCARDIAL STUNNING PROPERTIES” • Only intravenous positive inotrope that has had amortality benefit consistently. • Uniform physiological benefits for coronary, renal and G.I systems.

26. COMPARISON BETWEEN LEVOSIMENDAN, MILRINONE AND DOBUTAMINE

28. Risks of Inotropes and Vasopressors in CS Van Diepen S. J Am Coll Cardiol. 2018;72(2):183

29. What Do The ESC Guidelines 2016Say?

30. What Do The ESC GuidelinesSay?

31. Emergency Management of Complicated STEMI Clinical signs: Shock, hypoperfusion, congestive heart failure, acute pulmonary edema Most likely major underlying disturbance? Hypovolemia Low Output - Cardiogenic Shock Arrhythmia AcutePulmonary Edema • 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 Bradycardia Tachycardia • Administer • Fluids • Blood transfusions • Cause-specific interventions • Consider vasopressors Check Blood Pressure First line of action See Section 7.7 in the ACC/AHA Guidelines for Patients With ST-Elevation Myocardial Infarction Check Blood Pressure 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 Systolic BP Greater than 100 mm Hg and not less than 30 mm Hg below baseline Second line of action Norepinephrine 0.5 to 30 mcg/min IV Nitroglycerin 10 to 20 mcg/min IV Dobutamine 2 to 20 mcg/kg per minute IV Dopamine 5 to 15 mcg/kg per minute IV ACE Inhibitors Short-acting agent such as captopril (1 to 6.25 mg) 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 Circulation 2000;102(suppl I):I-172-I-216. Third line of action

32. Antmen, JACC, 2004;44:671

33. Inotropes andVasopressors 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 milrinonemay improve cardiac output. • Levosimendanmay be preferable if patient on chronic BB.

34. Newer Inotropic Agents • Cardiac myosin activators- Omecamtivemecarbil. • Na/K-ATPase inhibitors- Istaroxime. • Ryanodine receptorstabilizersJTV-519(K201), • S107, • S44121 • SERCA2a activators- • MYDICAR

36. New inotropicagents • Istaroxime: • Inotropic effect ∼inhibition of Na-K ATPase • Lusitropic effect ∼stimulation of SERCA 2a. • ↑ systolic blood pressure. • ↓ heart rate. • Myosinactivators • (e.g. Omecamtivmecarbil): • ↑ rate of effective myosin cross-bridgeformation. • → ↑ duration of myocytecontraction. • No effect on cAMP orcalcium. Hasenfuss, et al. Eur Heart J2011;32:1838-1845

37. 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

38. Novel therapies OmecamtivMecarbil[cardiac myosin activators] Cleland JG, Teerlink JR, Senior R, et al. The effects of the cardiac myosin activator, omecamtivmecarbil, 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 • 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

39. Effect of Tilarginine Acetate in Patients With Acute Myocardial Infarction and Cardiogenic Shock The TRIUMPH Randomized Controlled Trial 70% 60% 50% 40% 30% 20% 10% 0% Tilarginine 48% 42% 30 day-Mortality 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.

40. 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.

41. 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.

42. 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.

43. 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.

44. 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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