Fundamentals of critical care - vasoactive agents

Brief overview on vasoactives in PICU population

1. Fundamentals of Critical Care Medicine: Vasoactive Agents Rob Parker, DO 3/10/2017

2. Overview Adrenergic and Dopaminergic Subtypes Basic Properties HR Effect BP Effect Adrenergic receptors Alpha1 Alpha2 Beta Mixed Dopamine Vasopressin Milrinone Dobutamine Dopamine Vasopressin Milrinone Digoxin Nitroprusside/Nitroglycerine Novel Agents  Questions 2

3. Adrenergic and dopaminergic subtypes with respective G proteins and cellular effectors 3

4. The Autonomic Nervous System 4

5. Catecholamines Sympathomimetic amines that contain O- dihydrobenzene Dopamine, epinephrine and norepinephrine are endogenous Dobutamine and isoproterenol are synthetic 5

6. Catecholamine Synthesis Tyrosine is converted to dopa within the cytoplasm by the rate limiting enzyme tyrosine hydroxylase ( TH ). High levels of norepinephrine inhibit TH. Dopa is decarboxylated by aromatic amino acid decarboxylase ( AAD ) to produce dopamine. Dopamine enters the storage vesicle and is b - hydroxylated by dopamine b - hydroxylase ( D b H ) to produce norepinephrine. Approximately 85% of norepinephrine entering the adrenal medulla is converted to epinephrine by phenylethanolamine N -methyltransferase (PE N -M) 6

7. Definitions Pressor: increase systemic vascular resistance  blood pressure Inotrope: increase force of cardiac contractility ( dP / dt )  stroke volume Chronotrope : increase heart rate Lusitrope : improve diastolic relaxation  decreased End Diastolic pressure Vasodilator: decreases SVR and afterload Inodilator : improves contractility AND decreases afterload 7

8. Examples Pressor: increase SVR Phenylephrine, Vasopressin Inotrope: increase dP / dt DoButamine , Epi Chronotrope : increase HR Isoproterenol Lusitrope : improve relaxation Milrinone Vasodilator: decreases SVR Nitroprusside Inodilator : ↑ dP / dt AND ↓SVR Milrinone 8

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10. Adrenergic Receptors 10

11. 11 Jentzer JC, Coons JC, Link CB, Schmidhofer M. Pharmacotherapy update on the use of vasopressors and inotropes in the intensive care unit. J Cardiovasc Pharmacol Ther . 2015;20(3):249-60.

12. Adrenergic Agonists Adverse effects CVS: tachycardia, tachyarrhythmia's, myocardial ischemia, myocardial infarction GI: splanchnic hypoperfusion (stress ulceration, ileus, malabsorption, bowel infarction) Periphery: limb ischemia, necrosis Metabolic: hyperlactatemia, hyperglycemia Immune suppression (Dopamine) 12

13. Adrenergic Receptor Activity Desensitization: less bang for buck Decreased sensitization in chronic use or with chronic stress Sequestration: less exposed on surface Unpresented receptors at surface Down-Regulation: less # of receptors *Steroids can increase the surface presentation (fast) and absolute production (slow 4-6hrs) 13

14. Overview 14

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16. Specific Types

17. Alpha 1 17 Phospholipase C hydrolyzes PIP2 to IP3 and 1,2DG  IP3 and 1,2DG activity promote increased intracellular Ca+  Vasoconstriction

18. Phenylephrine (++++ a 1) Basics Pure alpha agonist Structurally similar to epinephrine but lacks hydroxy group Rapid onset and short duration (5-10 min) Clinical Effects Significant arterial vasoconstriction  elevated SVR No ionotropic properties Minor beta effects at massive doses Clinical Indications Cases of hypotension potentially from spinal shock or during spinal anesthesia Elevation of SVR and promotion of pulmonary blood flow ( ie . shunt physiology during a Tet Spell) Adverse Effects End organ perfusion specifically renal perfusion 18

19. Other Alpha 1’s Midrodine Prodrug, poorly diffuses across the BBB Used in symptomatic tx of orthostatic hypotension Oxymetazoline OTC nasal spray Methoxamine 19

20. Alpha 2 20 a2 presynaptic nerve terminal receptor binding  Gi protein releases GDP, binds GTP  Adenylate cyclase inhibited  Decreased cAMP  Decreased protein kinase activity  Inhibition of NE release

21. Clonidine Basics Centrally acting alpha 2 that decreases sympathetic outflow by inhibiting the release of NE Leads to lower peripheral vascular resistance and HR Can provide some analgesia Oral onset (1-3 hrs ), t 1/2 (8-12 hrs ); Transderma onset 2-3 days), t 1/2 (~20hrs) Clinical Effects Lowers HR and BP Clinical Indications Hypertension ADHD Withdrawal from other medications (benzo, opioids) Adverse Effects Dizziness, hypotension, drymouth , constipation, elevated LFT’s Can cause rebound HTN with abrupt withdrawal 21

22. Beta receptor 22 b1 myocardial receptor binding  Activation of Gs protein  Adenylate cyclase stimulated  Increased cAMP  Increased protein kinase activity  Increases phosphorylation of proteins associated with Ca+ channels  Increase in the extrusion Ca+ out of the sarcoplasmic reticulum  enhanced responsiveness of cardiac contractile proteins  Increased inotropy and chronotropy .

23. Isoproterenol (+++ b 1, +++ b 2) Basics Synthetic derivative of NE where an isopropyl group is added to the N –terminal Metabolized in liver and kidney No alpha activity Onset is immediate and t 1/2 is <15 min Clinical Effects Causes pure increased inotropy and chronotropy with a subsequent decrease in SVR Causes tachycardia, and bronchodilation with a decrease in PVR Clinical Indications Refractory bradycardia (especially in transplanted hearts) AV nodal block Adverse Effects Contraindicated in LVOTO due to increasing outflow tract gradient Avoid in pts with low diastolic pressures  myocardial ischemia Contraindicated in ischemic heart disease 23

24. Mixed Activity – Alpha and Beta 24

25. Norepinephrine (++++ a 1, + b 1) Basics: Primary neurotransmitter of sympathetic nervous system Formed in the adrenal medulla: Tyrosine + tyrosine hydroxylase  DOPA + dopa decarboxylase  Dopamine + dopamine beta-hydroxylase  NE Degraded in liver or kidney; or can be cleared by uptake at nerve terminals throughout body Short t 1/2 of 2-5 min Clinical Effects Primarily alpha causing increased SVR, increased myocardial oxygen consumption, and elevated mean pressures Without significant changes in ionotropy or chronotropy Clinical Indications Hyperdynamic septic shock Neurogenic shock Anaphylactic shock TCA toxicity causing a shocklike state Adverse Effects Increased myocardial oxygen consumption through increased afterload May decrease end organ perfusion if not adequate volume load prior to start Extravasation can lead to severe tissue necrosis (may be treated with phentolamine locally) 25

26. Epinephrine (++ a 1, +++ b 1, ++ b 2) Basics Endogenous catecholamine formed by the addition of a methyl group to NE NE + phenylethanolamine N-methyltransferase  EPI Synthesis occurs primarily in the adrenal medulla Short t 1/2 (2-3 min) Prominent hemodynamic effects as well as increasing ketogenesis and glucolysis Clinical Effects Dose Dependent Low dose: b 1> b 2> a 1 leading to chronotropy , inotropy, and a modest decrease in SVR High dose: a 1 and b 1 predominate  increased SVR, chronotropy and inotropy Can improve coronary and cerebral perfusion pressures Clinical Indications Vasoactive agent of choice in cardiac arrest Low cardiac output syndrome Hypotension from cardiac shock, hypodynamic septic shock and post arrest Anaphylaxis in setting of myocardial dysfuction Epi with vasodilator (nitroprusside) can improve distal perfusion in high SVR, low output states Adverse Effects Increased myocardial oxygen consumption Can cause myocardial ischemia Arrythmogenic Can increase potassium glucose and potassium levels 26

27. Dobutamine (+ a 1, +++ b 1, + b 2) Basics Synthetic catecholamine consisting of 2 racemic mixtures (+) isomer: strong b 1;  2 agonist and a 1 antagonist (-) isomer: weak b 1;  1 and 2 agonist T 1/2 is 2-3 min Clinical Effects Significant inotropy with trivial, if any, vasoconstriction b 2 effects can decrease SVR but more likely from sympathetic withdrawal upon return of cardiac function Less likely to produce arrythymias Can improve lusitropy  CO,  Preload,  MAP Clinical indications Useful for failing heart in congestive failure Mainly heart rate and contractility effects Adverse Effects Increased myocardial oxygen consumption Ischemia with high doses 27

28. Dopamine (D1, D2, a 1, b 1, b 2) Basics Intermediary compound in the production of EPI and NE Synthesized in nerve terminals of CNS and PNS, as well as adrenal medulla Metabolized in liver and kidney T 1/2 is ~2 min 30% plasma bound D1 binding  activation of Gs protein and AC  AC causes increased cAMP and PKA activity  vasodilation of select vascular beds D2 binding  activation of Gi protein with decrease in cAMP and decreased neurotransmitter release Clinical Effects Dose effect: Low dose (1–5 mcg/kg/min) D1> b > a 1: Renal/splanchnic vasodilation, naturesis Intermediate dose (4–8 mcg/kg/min) b > a 1> D1: Increased inotropy/ chronotropy High dose (> 10 mcg/kg/min) a 1> b > D1: Increased SVR, PVR Clinical Indications Used for children who have moderate cardiac and vascular dysfunction despite adequate fluid resuscitation Often first line because of its safety profile given peripherally No evidence to support use of renal dose dopamine Adverse Effects At high doses, may impair end organ perfusion Can cause extravasation and dysrhythmias May increase shunting and V/Q mismatch Concern that it may impair immune function; can suppress TSH release prolonging sick euthyroid 28

29. Vasopressin Basics: Peptide hormone released by paraventricular nucleus of the hypothalamus and transported via neuronal axons to the posterior pituitary for secretion Released in response to hemodynamic, osmotic and nonosmotic stimuli (stress, pain, nausea, hypoxia, hypercarbia)  result in free water conservation and SIADH With low BP, can cause appropriate ADH release T1/2 is 6-20 min Clinical Effects V1a receptors binding causes activation of PLC-Inositol pathway leading to increased cytosolic Ca+ release  vasoconstriction Can also block K-ATP channels  increased Ca+  vasoconstriction V1b increase ACTH and endorphins V2 receptors are found on renal tubule cells and mediate antidiuresis through increased water permeability and water resorption in the collecting tubules No direct cardiac effects but can decrease CO by increasing SVR causing reflexively decreased HR Clinical Indications Refractory vasodilatory shock – potentially no better than other agents Treatment of diabetes insipidis Adverse effects CVS: myocardial ischemia GI: splanchnic hypoperfusion Hepatic:  bilirubin during infusion Periphery: limb ischemia, necrosis 29

30. Phosphodiesterase Inhibitors - Milrinone 30 Inhibition of phosphodiesterase III leads to sustained cAMP levels, subsequent increased phosphokinase activity and ultimately increased myocardial cytosolic calcium and decreased endothelial cytosolic calcium. The net clinical effect is increased inotropy and vasodilation

31. Milrinone Basics Bipyridine phopshodiesterase III inhibitor Inhibition of PDE III  reduction in cAMP breakdown  increased myocardial cytosolic concentrations of cAMP  increased myocardial cytosolic calcium, decreased endothelial cytosolic calcium  inhibition of myosin light chain activity in vascular endothelium. T 1/2 : 2-3 hours Excretion: unchanged by kidney with small amount metabolized by liver Clinical Effects Results in increased inotropy, lusitropy and vasodilation  increased CO MAP usually maintained through increased contractility and SV Anti-inflammatory effects Clinical Indications DOC for primary myocardial dysfunction (cardiomyopathies, post-op) Adverse effects CVS Hypotension (especially in bolus form) Tachycardia, tachyarrhythmias (SVT) Hematologic: Thrombocytopenia 31

32. Digoxin Basics Cardiac glycoside Binds and blocks the Na+- K+ ATPase located in the myocardial sarcolemma  increase in Ca+  increase contractility Can be affected by potassium levels (hyper  decreased binding; hypo  increased binding) Onset (2-6hrs oral, 15-30 min IV) Clinical Effects Direct inotropy and negative chronotropy In healthy heart  increased SVR In failing heart  decrease SVR through lowering sympathetic tone Clinical Indications No role in acute management Often used for longterm myocardial support in conjunction with diuretics and afterload reducers Can be useful in some atrial arrhythmias Adverse Effects GI disturbances that are centrally mediated Headache, pain, fatigue and visual disturbances Cardiac toxicity – profound bradycardia, AV block, SVT and VT,, prolonged PR, ST segment sagging, small T wave Many drug interactions Potentiated by renal failure 32

33. Nitric Oxide Donors – Nitroglycerine, Nitroprusside, Isosorbide Basics: Produce relaxation of both venous and arterial smooth muscle Lowers SVR and afterload In healthy hearts  lower preload  lower CO In sick hearts  less afterload  higher CO Pharmacology: Stimulates guanylate cyclase to produce a rise in intracellular cGMP. Leads to an increase in cGMP-dependent protein kinase activity, which causes a decrease in Ca++ influx and ultimately vasodilation Pharmacokinetics: Very rapid onset of action (less than 30 seconds) and a 5–10 minute half-life Its effects dissipate within 3 minutes of discontinuation Adverse Effects: Tox : rapidly forms cyanide and methemoglobin CNS: headaches, dizziness,  cerebral perfusion CVS: hypotension, reflex tachycardia,  coronary perfusion Skin: flushing 33

34. Novel Agents Levosimendan Calcium-sensitizing agent that produces inodilator effects Increases myofilament calcium sensitivity by binding to cardiac troponin C Causes opening of ATP-sensitive potassium channels in vascular smooth muscle leading to relaxation and vasodilation Very long acting (t 1/2 80hrs as prodrug) Causes increased CO without increasing myocardial oxygen consumption Nesiritide Recombinant form of endogenous BNP Causes an increase in cGMP in vascular smooth muscle resulting vasodilation and a reduction in afterload without reflex tachycardia Suppresses the renin–angiotensin–aldosterone and promotes diuresis and natriureis Used in severe heart failure Tolvaptan Selective V2 receptor antagonist that acts on the distal nephron to increase free water excretion and aid in the correction of heart failure induced hyponatremia Not approved for pediatric use 34

35. Questions 35

36. Next 3 Graphs For a 1 y.o . patient with sepsis syndrome and shock of unclear etiology has received 60 mL/kg of fluid and you are consulted: the HR is 160/min, BP 80/40 and a medication was started. What medication is the most consistent with the following changes in BP, HR, Contractility and Filling pressure: a. Dopamine d. Vasopressin b. Dobutamine e. Nitroprusside c. Milrinone 36

37. Problem 1 – What medication? Dopamine? Dobutamine? Milrinone? Vasopressin? Nitroprusside? Blood Pressure and Heart Rate Contractility and Filling Pressure 37

38. Problem 2 – What medication? Dopamine? Dobutamine? Milrinone? Vasopressin? Nitroprusside? Blood Pressure and Heart Rate Contractility and Filling Pressure 38

39. Problem 3 – What medication? Dopamine? Dobutamine? Milrinone? Vasopressin? Nitroprusside? Blood Pressure and Heart Rate Contractility and Filling Pressure 39

40. 6 month, 5 kg, infant with sepsis syndrome, shock and hypotension Improving on 220 mL/kg isotonic crystalloid over 12 hours Escalating vent settings with SpO2 98%, SvO2 60% Dopamine infusion at 20 mcg/kg/min No UOP x 2 Hr T 39C, P 110/min, RR 40, BP 48/18 mmHg, Cap Refill > 5sec, CVP is 20 mmHg 40

41. Which of the following medication infusions would be the BEST choice? Furosemide at 0.1 to 0.5 mg/kg/hour titrated to urine output Sodium Nitroprusside at 1-8 mcg/kg/minute titrated to perfusion Epinephrine at 0.1 to 1 mcg/kg/minute titrated to perfusion Increase the dopamine infusion to 40 mcg/kg/minute titrated to perfusion Insert an intra-aortic balloon pump and titrate to perfusion 41 HR 110/min BP 48/18 CVP 20mmHg SvO2 60% Cap Refill 5 sec No UOP >2hr

42. 6 month, 5 kg, infant with dilated cardiomyopathy and hypotension Worsening with 20 mL/kg isotonic crystalloid over 2 hours Escalating vent settings with SpO2 98%, SvO2 60% Dopamine infusion at 20 mcg/kg/min No UO x 2 Hr T 39C, P 180/min (ST), RR 40, BP 48/18 mmHg, Cap Refill >5sec, CVP is 25 mmHg 42

43. Which of the following medication infusions would be the BEST choice? Inotrope alone (Epinephrine or Isoproterenol) Inodilator bolus (Milrinone) Vasopressor alone (Phenylephrine or Vasopressin) Dopamine and low dose inodilator infusion Beta-blocker ( esmolol ) to slow the HR 43 HR 180/min BP 48/18 CVP 25mmHg SvO2 60% Cap Refill 5 sec No UOP >2hr

44. 7 year old with traumatic brain injury, pulmonary contusion and pARDS ICP 10-20; no fracture or bleed on CT Pupils equal and reactive Bedside ABG shows metabolic acidosis (pH 7.10, pCO2 28) T 36C, P 170/min (ST), RR 25 (vent) on propofol 60 mcg/kg/min BP 70/30, MAP 45mm Hg ETCO2 35, SpO2 98% CVP 10, ICP presently 20, CPP 25mm Hg 44

45. Case Progression The CVP rises to 15 cmH2O without other changes after 10mL/kg isotonic crystalloid and dopamine at 10 mcg/kg/min Decrease in propofol resulted in coughing and movement with increased ICP, but no change in BP. He was switched to an alternative sedative regimen. 45

46. Which of the following medication infusions would be the BEST choice? Norepinephrine at 0.1-1.0 mcg/kg/min titrated to perfusion and BP Additional fluid boluses until the CVP is 25 cmH20 Epinephrine at 0.05-1 mcg/kg/minute titrated to perfusion Increase the dopamine infusion to 40 mcg/kg/minute titrated to perfusion Intra-aortic balloon pump 46 HR 170/min BP 70/30 MAP 45mmHg ICP 20cmH2O CVP 15mmHg SpO2 98%

47. For a 6 mo. patient with dilated cardiomyopathy, HR 180/min (ST), CVP of 20mmHg, BP 110/90 mmHg, rising lactate and SvO2 of 55%, and capillary refill of 5 seconds, what would you consider the best treatment option? Inotrope (Epinephrine) Inodilator bolus and infusion (milrinone) Vasopressor (Phenylephrine or Vasopressin) Fluid bolus Beta- blocker ( esmolol ) to slow the HR 47

48. For a 6 mo. patient with septic shock after 100cc/kg volume resuscitation, HR 180/min (ST), CVP 20mmHg, BP 50/20 mmHg, rising lactate and SvO2 of 55%, on dopamine of 10mcg/kg/min and capillary refill of 1 second, what would you consider the best treatment option? Inotrope (Low dose Epinephrine) Inodilator infusion (milrinone) Vasopressor (Norepinephrine or Vasopressin) Fluid bolus Beta- blocker ( esmolol ) to slow the HR 48

49. Label the parts of the curve 49 Diastolic Filling Isovolumetric Contraction Ejection Isovolumetric Relaxation M. Mitral Valve Closes A. Aortic Valve Opens A. Aortic Valve Closes M. Mitral Valve Opens

50. Question The left ventricle pressure-volume curve at times A and B is shown in the figure. The increase in stroke volume shown at time B is due to which of the following factors? Increased contractility Increased preload Decreased afterload Improved lusitropy 50

51. Question The red curve represents: Increased inotropy Increased preload Decreased Stroke Volume Decreased afterload 51

52. For each diagnosis, select the left ventricular pressure-volume loop most likely to be obtained. Aortic stenosis Curve A Curve B Curve C Curve D Curve E 52

53. For each diagnosis, select the left ventricular pressure-volume loop most likely to be obtained. VSD Curve A Curve B Curve C Curve D Curve E 53

54. Dosing and Titration 54

55. 55