1. Vasoactive Agents in the PICU
PCCM Faculty
University of North Carolina
Pediatric Critical Care Medicine

2. Outline Developmental physiology of cardiovascular system
Basic terminology review
Description of most commonly used agents by site and mechanism of action

3. What this will not teach you
Will not review specific algorithms (i.e.-sepsis, low cardiac output syndrome, anaphylaxis, etc) in detail

4. Developmental Physiology

5. Myocardial Contraction
Contractility increases over 1st months of life along with:
#’s of sympathetic nerve fibers within myocardium
Total concentration of endogenous norepinephrine
There is a greater dependence of CO on HR than contractility during this time

6. Immature Heart Limited responsiveness to medications
 noncontractile content
 availability of releasable NE
Less mature sympathetic system
Underdeveloped intracellular calcium regulatory mechanisms
 functional reserve capacity

7. Ionized Calcium
Plays central role in maintaining myocardial contractility
Effects mediated via intracellular concentration, calcium requirements of the muscle cell, sensitivity of the myofilaments to calcium

8. 1
Membrane depol of the myocardial sarcolemma allows influx of “trigger” calcium across the voltage gated calcium channels of the transverse tubule.
This then activates th “calcium induced calcium mediated release” across the ryanodine receptor (RyR)-mediated calcium release of the sarcoplasmic reticulum.
Cytosolic calcium binds to the troponin C of the myofilaments allowing the contractile process to begin
Dissociation of calcium from this complex initiates relaxation and released calcium is then sequestered by the calcium-ATPase within the sarcoplasmic reticulum
Multiple cAMP-dependent protein kinasesexist in myocardial cells.
Phosphorylation of the sites on the sarcolemma, sarcoplasmic reticulum, and troponin complex results in an influx of calcium across the sarcolemma, acceleration of calcium uptake by the sarcoplasmic reticulum, and an increased rate of dissociation of calcium from troponin C. By increasing intracellular cAMP, myocardial contractility is improved.

9. Vascular Smooth Muscle
Calcium dependent effects
Agents that increase intracellular cAMP increase intracellular calcium requirements for contraction, thus encouraging smooth muscle relaxation and vasodilation

10. Vascular Smooth Muscle
Calcium independent effects
G protein mediated activation of phospholipase C results in breakdown of phosphatidylinositol bisphosphate into IP3 and DAG.
IP3 releases calcium from the sarcoplasmic reticulum initiating contraction and DAG activates protein kinase C with phosphorylation of intracellular proteins

11. Effects of Agents
Pressors: increase systemic vascular resistance and increase blood pressure
Inotropes: affect myocardial contractility and enhance stroke volume
Chronotropic Agents: affect heart rate
Lusotropic Agents: improve relaxation during diastole and decrease EDP in the ventricles
Dromotropic Agents: Affects conduction speed through AV node; increases heart rate
Bathmotropic Agents: affect degree of excitability

12. Alpha-Adrenergic Agents
Alpha1-adrenergic effects:
Vascular smooth muscle contraction
Alpha2-adrenergic effects:
Vascular smooth muscle relaxation

13. Beta-Adrenergic Agents
Beta1-adrenergic effects:
Direct cardiac effects
Inotropy (improved cardiac contractility)
Chronotropy (increased heart rate)
Beta2-adrenergic effects:
Vasodilation
Bronchodilation

14. Dopaminergic Agents Dopaminergic Agents
Several types of receptors located throughout body (D1-D5)
Certain (esp. D1-like & D2-like) dopaminergic receptors increase renal and mesenteric blood flow

15. Catecholamines Sympathomimetic amines that contain O-dihydrobenzene
Dopamine, epinephrine and norepinephrine are endogenous
Dobutamine and isoproterenol are synthetic
Sustained use or antecedent CHF can lead to down-regulation of β-receptors and decrease efficacy

17. Epinephrine
Both an alpha- and beta-adrenergic agent 0.01 mcg/kg/min-0.3 mcg/kg/min
Low-dose infusion = β activation
Increase HR, contractility, decrease SVR
Higher doses =  activation
Increased SVR and MAP
Increased myocardial O2 demand

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

19. Epinephrine Indications for its use as a continuous infusion are:
low cardiac output state
beta effects will improve cardiac function
alpha effects may increase afterload and decrease cardiac output
septic shock
useful for both inotropy and vasoconstriction

20. Epinephrine Adverse effects include: Anxiety, tremors,palpitations
Tachycardia and tachyarrhythmias
Increased myocardial oxygen requirements and potential to cause ischemia
Decreased splanchnic and hepatic circulation (elevation of AST and ALT)
Anti-Insulin effects: lactic acidosis, hyperglycemia

21. Norepinephrine
An epinephrine precursor that acts primarily on  receptors
Used primarily for alpha agonist effect - increases SVR without significantly increasing C.O.
Used in cases of low SVR and hypotension such as profound “warm shock” with a normal or high C.O. state- usually in combination with dopamine or epinephrine
Infusion rates titrated between 0.05 to 0.3 mcg/kg/min

22. Norepinephrine
Differs from epinephrine in that the vasoconstriction outweighs any increase in cardiac output.
i.e. norepinephrine usually increases blood pressure and SVR, often without increasing cardiac output.

23. Norepinephrine Adverse Effects: Similar to those of Epinephrine
Can compromise perfusion in extremities and may need to be combined with a vasodilator e.g. Dobutamine or Nipride
More profound effect on splanchnic circulation and myocardial oxygen consumption

24. Vasopressin
a peptide hormone released by the posterior pituitary in response to rising plasma tonicity or falling blood pressure
possesses antidiuretic and vasopressor properties
deficiency of this hormone results in diabetes insipidus

25. Vasopressin

26. Vasopressin Administration
intravenous, intramuscular, or intranasal routes
IV is route for vasopressor activity
The half-life of circulating ADH is approximately 20 minutes, with renal and hepatic catabolism via reduction of the disulfide bond and peptide cleavage

27. Vasopressin Administration Newer drug to ACLS for resuscitation
interacts with two types of receptors
V1 receptors are found on vascular smooth muscle cells and mediate vasoconstriction
V2 receptors are found on renal tubule cells and mediate antidiuresis through increased water permeability and water resorption in the collecting tubules
Newer drug to ACLS for resuscitation
Use in refractory septic shock with low SVRI in pediatrics?

28. Dopamine
Intermediate product in the enzymatic pathway leading to the production of norepinephrine; thus, it indirectly acts by releasing norepinephrine.
Directly has ,  and dopaminergic actions which are dose-dependent.
Indications are based on the adrenergic actions desired.

29. Dopamine
 renal perfusion 2-5 mcg/kg/min (dopaminergic effects) by  sensitivity of vascular smooth muscle to intracellular calcium (? Effects on UOP)
 C.O. in Cardiogenic or Distributive Shock 5-10mcg/kg/min ( adrenergic effects)
Post-resuscitation stabilization in patients with hypotension (with fluid therapy) 10-20mcg/kg/min ( adrenergic effects) peripheral vasoconstriction,  SVR, PVR, HR, and BP—This dose may be needed in preterm infants for medium dose effects

30. Dose Dependent effect of Dopamine
<5 mcg
mcg
> 10 mcg
↑ HR,
Vasoconstriction
↑/ ↓ Renal BF
↓/↑ Splanchnic BF
Modest ↑ CO
↑ Renal BF
↓Proximal Tub. Na
Absorbtion
↑ Splanchnic BF
↑Contractility
Minimal change in
HR and SVR
↑ Renal BF
↑ Splanchnic BF

31. Dobutamine
Synthetic catecholamine with 1 inotropic effect (increases stroke volume) and 2 peripheral vasodilation (decreases afterload)
Positive chronotropic effect 1 (increases HR)
Some lusotropic effect
Overall, improves Cardiac Output by above beta-agonist acitivity

32. Dobutamine
Major metabolite is 3-O-methyldobutamine, a potent inhibitor of alpha-adrenoceptors.
Therefore, vasodilation is possible secondary to this metabolite.
Usual starting infusion rate is mcg/kg/min, with the dose being titrated to effect up to 20 mcg/kg/min.

33. DOBUTAMINE Dobutamine Stimulates β1 and β2 Stimulates α1 D- isomer
L- isomer
Stimulates α1

34. Dobutamine
Used in low C.O. states and CHF e.g. myocarditis, cardiomyopathy, myocardial infarction
If BP adequate, can be combined with afterload reducer (Nipride or ACE inhibitor)
In combination with Epi/Norepi in profound shock states to improve Cardiac Output and provide some peripheral vasodilatation

35. Isoproterenol Synthetic catecholamine
Non-specific beta agonist with minimal alpha-adrenergic effects.
Causes inotropy, chronotropy, and systemic and pulmonary vasodilatation.
Indications: bradycardia, decreased cardiac output, bronchospasm (bronchodilator).

36. Isoproterenol
Occasionally used to maintain heart rate following heart transplantation.
Dose starts at 0.01 mcg/kg/min and is increased to 2.0 mcg/kg/min for desired effect.
Avoid in patients with subaortic stenosis, and hypertrophic cardiomyopathy or TOF lesions because increases the outflow gradient

37. Milrinone/Amrinone Belong to class of agents “Bipyridines”
Non-receptor mediated activity based on selective inhibition of Phosphodiesterase Type III enzyme resulting in cAMP accumulation in myocardium
cAMP increases force of contraction and rate and extent of relaxation of myocardium
Inotropic, vasodilator and lusotropic effect
Advantage over catecholamines:
Independent action from -receptor activation, particularly when these receptors are downregulated (CHF and chronic catecholamine use)

38. Milrinone
Increases CO by improving contractility, decreased SVR, PVR, lusotropic effect; decreased preload due to vasodilatation
Unique in beneficial effects on RV function
Protein binding: 70%
Half-life is 1-4 hours
Elimination: primarily renally excreted
Load with 50 mcg/kg over 30 mins followed by 0.25 to 0.75 mcg/kg/min
No increase in myocardial O2 requirement

39. PDE Inhibition
PDE
PDE 3
PDE 5
Aminophylline
Milrinone
Sildenefil

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

41. Other Vasoactive Agents

42. NESRITIDE Recombinant hBNP
Secreted by ventricles in response to ↑ wall stress and volume overload
Venous and arteriolar dilator, acts on Guanylate cyclase
It reduces RA pressure, PCWP and cardiac index
Dose: Infusion mcg/kg/min
Hypotension

43. Nesiritide: Other Effects
Nesiritide (recombinant human BNP) is a vasodilator with other theoretical effects including:
natriuresis, neurohormonal inhibition, and reverse remodeling
In the setting of Heart Failure, it has been shown to reduce pulmonary capillary wedge pressure and improve shortness of breath relative to placebo
Linked to possible renal failure and increased mortality in some patient populations

44. Vasodilators Classified by site of action
Venodilators: reduce preload - Nitroglycerin
Arteriolar dilators: reduce afterload Minoxidil and Hydralazine
Combined: act on both arterial and venous beds and reduce both pre- and afterload Sodium Nitroprusside (Nipride)

45. Nitroprusside
Vasodilator that acts directly on arterial and venous vascular smooth muscle.
Indicated in hypertension and low cardiac output states with increased SVR.
Also used in post-operative cardiac surgery to decrease afterload on an injured heart.
Action is immediate; half-life is short; titratable action.

46. Nitroprusside
Toxicity is with cyanide, one of the metabolites of the breakdown of nipride.
Severe, unexplained metabolic acidosis might suggest cyanide toxicity.
Dose starts at 0.5 mcg/kg/min and titrate to 5 mcg/kg/min to desired effect. May go higher (up to 10 mcg/kg/min) for short periods of time.

47. Nitroglycerine
Direct vasodilator as well, but the major effect is as a venodilator with lesser effect on arterioles.
Not as effective as nitroprusside in lowering blood pressure.
Another potential benefit is relaxation of the coronary arteries, thus improving myocardial regional blood flow and myocardial oxygen demand.

48. Nitroglycerine
Used to improve myocardial perfusion following cardiac surgery
Dose ranges from 0.5 to 8 mcg/kg/min. Typical dose is 2 mcg/kg/min for 24 to 48 hours post-operatively
Methemoglobinemia is potential side effect

49. Summary

50. Relative receptor activity of most commonly used inotropesα1 α2 β1 β2 DA
Norepinephrine
+++ + -
Epinephrine ++
Dopamine
Dobutamine
Isoproterenol

51. Receptor Activity (continued)