A Practical Approach to Ionotropes and vasopressors

Vasopressors are a powerful class of drugs that induce vasoconstriction and Inotropes increase cardiac contractility. Choice of an agent should be based upon the suspected underlying etiology of shock.
This presentation deals with the practical issues and controversies surrounding the use of these agents

1. Dr. Aneesh T Assistant Professor Dept. of General Medicine Inotropes & Vasopressors A Practical approach to

2. Overview

3. Introduction Vasopressors are a powerful class of drugs that induce vasoconstriction and thereby elevate mean arterial pressure (MAP ) Inotropes  increase cardiac contractility However, many drugs have both effects. Quite a few agents  only some controlled clinical trials have directly compared these agents T he manner in which these agents are used largely reflects… Expert opinion Animal data Tissue oxygenation

4. Receptor physiology The main categories of receptors relevant to vasopressor & inotropic activity are α 1 (Alpha 1) β 1 (Beta 1) β 2 (Beta 2) Dopamine Calcium sensitizers Located in vascular walls I nduces significant vasoconstriction Also present in the heart - increases duration contraction

5. Receptor physiology The main categories of receptors relevant to vasopressor & inotropic activity are α 1 (Alpha 1) β 1 (Beta 1) β 2 (Beta 2) Dopamine Calcium sensitizers Increases in inotropy Increases chronotropy Minimal vasoconstriction

6. Receptor physiology The main categories of receptors relevant to vasopressor & inotropic activity are α 1 (Alpha 1) β 1 (Beta 1) β 2 (Beta 2) Dopamine Calcium sensitizers Blood vessels Located in several other locations Vasodilation

7. Receptor physiology The main categories of receptors relevant to vasopressor & inotropic activity are α 1 (Alpha 1) β 1 (Beta 1) β 2 (Beta 2) Dopamine Calcium sensitizers Renal , splanchnic, coronary, cerebral beds Dose dependent action Can induce noradrenaline release

8. Receptor physiology The main categories of receptors relevant to vasopressor & inotropic activity are α 1 (Alpha 1) β 1 (Beta 1) β 2 (Beta 2) Dopamine Calcium sensitizers Increases sensitivity of myocardium to Ca 2+ Also inhibit phosphodiesterase Increase inotropy and vasodilation

9. Principles

10. Principles Indications A decrease of >30 mm Hg from baseline systolic blood pressure A mean arterial pressure <60 mmHg when End-organ dysfunction ensues due to hypoperfusion Hypovolemia should be corrected prior to the institution of vasopressor therapy

11. Principles The rational use of vasopressors and inotropes is guided by three fundamental concepts

12. Practical issues I. Volume resuscitation Repletion of adequate intravascular volume - crucial prior to the initiation of vasopressors Most patients in septic shock – need ~2 liters of fluids Else, vasopressor effect is suboptimal or even ineffective Fluids withheld Pulmonary edema ARDS Heart failure PCWP or IVC ultrasound for monitoring (IVC diameter <2 cm may suggest volume depletion)

13. Practical issues II. Selection and titration Choice of an initial agent  underlying etiology of shock Dose should be titrated up to achieve effective blood pressure or end-organ perfusion – based on urine output or mentation Maximal doses of the first agent or evidences of adverse effects  add a second agent A third agent may be added – no controlled trials for this approach

14. Practical issues III. Route of administration Vasopressors and inotropic agents  via Central venous catheter CVC  Rapid delivery to the heart & peripheries & prevents extravasation Peripheral IV line – A temporary measure till a central line is achieved

15. Practical issues IV . Tachyphylaxis Responsiveness to these drugs can decrease over time due to tachyphylaxis . Constantly titrated to adjust for this phenomenon and for changes in the patient's clinical condition

16. Practical issues V . Hemodynamic effects Mean arterial pressure (MAP) is influenced by systemic vascular resistance ( SVR) and cardiac output (CO ) Eg . In cardiogenic shock, increasing SVR can increase afterload on an already failing heart  impairing CO Raising SVR is beneficial in septic shock, when cardiac function is largely normal.

17. Practical issues VI . Subcutaneous delivery of medications Critically ill patients often on sc medication (LMWH, insulin) The bioavailability of these medications - reduced during treatment with vasopressors due to cutaneous vasoconstriction . A higher dose of LMWH may be required for thrombosis prophylaxis May require switching to intravenous therapy

18. Practical issues VII. Frequent re-evaluation Critically ill patients may undergo a second hemodynamic insult Could necessitates a change in vasopressor or inotrope management The dosage of a given agent should not simply be increased without reconsideration of the clinical situation and the appropriateness of the current strategy Weaning Catechol Vasopressors are titrated quickly Inotropes ( Inamrinone , dobutamine ) are titrated over hours

19. Adrenergic agents Acts on both alpha1 and beta1 adrenergic receptors Potent vasoconstriction as well as a modest increase in cardiac output Thus the mild chronotropic effect is canceled out and the heart rate remains unchanged or even decreases slightly Preferred agent in septic shock Norepinephrine (Noradrenaline) ↑ MAP ↑ CO Reflex bradycardia

20. Adrenergic agents Initiating dose Maintenance dose Role in therapy 8 to 12 mcg/minute 2 to 4 mcg/minute Max : 35 - 100 mcg/minute Initial vasopressor of choice in septic, cardiogenic, and hypovolemic shock. Wide range of doses utilized clinically. Norepinephrine (Noradrenaline)

21. Adrenergic agents Norepinephrine (Noradrenaline) 1 ampoule = 2 ml (2mg/ml) i.e 4mg 2 amps in 46 ml NS/5D = 8 mg (8000 µg) in 50 ml 1ml of infusion = 160 µg Starting rate = 3 ml/ hr = 8 µg/min = 3 ml/ hr  40 µg/min = 15 ml/ hr 160x3 60

22. Adrenergic agents Potent β 1, moderate β 2 & α 1 adrenergic receptor effects . Clinically, low doses of ↑ CO ( β1 )  inotropic & chronotropic effects W hile α receptor induced vasoconstriction is offset by the β 2 mediated vasodilation . Net result (Low doses ) = ↑ CO with ↓ SVR & variable effects on MAP However, at higher doses the α effect predominates  increased SVR in addition to an increased CO Epinephrine ( Adrenaline)

23. Adrenergic agents Epinephrine ( Adrenaline) Initiating dose Maintenance dose Role in therapy 1 µg/minute 1 to 10 µg /minute Initial vasopressor of choice in anaphylactic shock. Add-on agent to norepinephrine in septic shock. Increases heart rate; may induce tachyarrhythmias and ischemia. Elevates lactate concentrations* May decrease mesenteric perfusion.

24. Adrenergic agents Adrenaline 1 ampoule = 1 ml (1:1000) i.e 1mg 1 amp in 49 ml NS/5D = 1 mg (1000 µg) in 50 ml 1ml of infusion = 40 µg Starting rate = 1.5 ml/ hr = 1 µg/min = 1.5 ml/ hr  10 µg/min = 15 ml/ hr 40x1.5 60

25. Adrenergic agents Dopamine E ffects depending upon the dose range administered 2 nd line agent to norepinephrine where there is a low risk of tachyarrhythmias . Dose Receptor action Result Clinical Effect 1 to 2 mcg/kg per minute Dopamine1 (D1) receptors in renal, mesenteric, cerebral, coronary beds Selective vasodilation Increases urine output by augmenting RBF & GFR

26. Adrenergic agents Dopamine Dose Receptor action Result Clinical Effect 5 to 10 mcg/kg per minute Beta1 adrenergic receptors ↑ CO and SVR ↑ HR increase in MAP >10 mcg/kg per minute Alpha adrenergic receptors Vasoconstriction with an ↑ SVR increase in MAP Max dose 20-50 mcg/kg per minute

27. Adrenergic agents Dopamine 1 ampoule = 5 ml (40 mg/ml) i.e 200 mg 2 amps in 46 ml NS/5D = 400 mg in 50 ml 1ml of infusion = 8 mg (8000 µg) 5 µg/kg/min  starting dose I n a 70 kg pt = 5x70 = 350 µg/min Starting rate = 3 ml/ hr = 5x70 µg/min ~ 400 µg/min = 3 ml/ hr = 35x70 µg/min ~ 18 ml/ hr 8000x3 60

28. Adrenergic agents Dobutamine Not a vasopressor An inotrope that causes vasodilation β 1 effect increases inotropy and chronotropy & reduces LV filling pressure Minimal α 1 & β 2 actions cause vasodilation The net effect  ↑ CO , ↓SVR ± small reduction in BP Indicated in severe, medically refractory heart failure and cardiogenic shock Sepsis

29. Adrenergic agents Dobutamine Initiating dose Maintenance dose Role in therapy 0.5 to 1 mcg/kg/min 2 to 20 mcg/kg/min Initial agent of choice in cardiogenic shock with low CO and maintained blood pressure Add-on to norepinephrine for CO augmentation in septic shock with myocardial dysfunction High risk for tachyarrhythmias

30. Adrenergic agents Dobutamine 1 ampoule = 5 ml (50 mg/ml) i.e 250 mg 1 amp in 45 ml NS/5D = 250mg in 50 ml 1ml of infusion = 5 mg (5000 µg) 1 µg/kg/min  starting dose I n a 70 kg pt = 70 µg/min Starting rate = 1 ml/ hr = 83.33µg/min = 3 ml/ hr = 20x70 µg/min ~ 18 ml/ hr (1400 µg/min) 5000x1 60

31. Adrenergic agents Phenylephrine Pure α  vasoconstriction with minimal cardiac inotropy or chronotropy MAP is augmented by raising systemic vascular resistance Useful situations for its use - hyperdynamic sepsis, neurologic disorders, anesthesia induced hypotension Disadvantage  reduces stroke volume (Reserved for use where noradrenaline cannot be given i.e. tachyarrhythmias )

32. Adrenergic agents Phenylephrine Initiating dose Maintenance dose Role in therapy 100 to 180 mcg/minute until stabilized 20 to 80 mcg/minute Pure alpha vasoconstrictor Initial vasopressor when tachyarrhythmias preclude use of noradrenaline Alternative agent in septic shock; despite use of 2 agents Useful in anesthesia related hypotension May decrease stroke volume and cardiac output in patients with cardiac dysfunction.

33. Adrenergic agents Vasopressin & Terlipressin A 2 nd line agent in refractory vasodilatory shock, i.e. septic shock or anaphylaxis Also used often to reduce the dose of the 1 st line agent 2 large meta-analyses revealed No short term mortality benefit However, reduced the dose of Noradrenaline Lesser rate of renal failure requiring replacement Rebound hypotension is common (needs tapering)

34. Adrenergic agents Vasopressin Initiating dose Maintenance dose Role in therapy 0.03 units per minute 0.03 to 0.04 units per minute (not titrated) Not recommended as a replacement for a 1 st line agent Pure vasoconstrictor; may precipitate ischemia in coronary artery disease.

35. Adrenergic agents Vasopressin 1 ampoule = 1 ml (20U/ml ) 20U 2 amps in 46 ml NS = 40 U in 50 ml 1ml of infusion = 0.8 U 0.03 U/min  starting dose Rate of Infusion = 2.5 ml/ hr = 0.033 U/min

36. Adrenergic agents Ephedrine Isoproterenol Post anesthesia induced hypotension Hypotension secondary to bradycardia

37. Non- Adrenergic agents PDE inhibitors I namrinone ( formerly known as amrinone ) and Milrinone inotropic and vasodilatory actions – akin to Dobutamine Lower risk of arrhythmias Used in medically refractory heart failure (limited by hypotension)

38. Non- Adrenergic agents NOS inhibitors N-monomethyl – arginine (L-NMMA) in sepsis demonstrate a dose dependent increase in SVR Cardiac index reduces – limits its use- even with other vasopressors Clinical utility - unproven Calcium sensitizers Pimobendan , Levosimendan - increase myocardial contractility Evidence of improved outcomes with their use is lacking

39. Controversies Stem from the relative paucity of large scale studies comparing similar patient populations treated with different regimens . 1. Choice of agent in septic shock Earlier – Dopamine was used A paradigm shift in practice has occurred -most experts prefer to avoid dopamine and favour noradrenaline

40. Controversies 2. "Renal dose" dopamine ↑ renal blood flow in normal volunteers at 1 - 3 mcg/kg/min A beneficial effect of low or "renal dose" dopamine - less proven in patients with sepsis Most effective means of protecting the kidneys in septic shock is to maintain MAP >60 mmHg

41. Controversies 3 . Supra-normal cardiac index Theoretically, ↑ cardiac index with inotropes to >4.5 L/min/m 2 (Supra-normal) potentially ↑ oxygen delivery to peripheral tissues . M ay prevent tissue hypoxia and improve outcomes Large trials - resulted in either no improvement or worsened morbidity or mortality Not advocated

42. Vasopressors - powerful class of drugs that induce vasoconstriction and elevate mean arterial pressure Vasopressors - indicated for a MAP <60 mmHg, or a drop of systolic BP >30 mmHg from baseline, when either condition results in endorgan dysfunction due to hypoperfusion Hypovolemia should be corrected prior to vasopressor therapy for maximum efficacy - reevaluated frequently once vasopressor therapy has been initiated Summary and Recommendations

43. Choice of an initial agent should be based upon the suspected underlying etiology of shock Complications of vasopressors  hypoperfusion , dysrhythmias, myocardial ischemia, peripheral extravasation with skin necrosis and hyperglycemia. Summary and Recommendations

44. Thank you