vasoactive agents in the picu pccm faculty university of north carolina pediatric critical care...

Vasoactive Agents Vasoactive Agents in the PICUin the PICU

PCCM FacultyPCCM Faculty

University of North CarolinaUniversity of North Carolina

Pediatric Critical Care MedicinePediatric Critical Care Medicine

OutlineOutline

Developmental physiology of Developmental physiology of cardiovascular systemcardiovascular system

Basic terminology reviewBasic terminology review

Description of most commonly used Description of most commonly used agents by site and mechanism of actionagents by site and mechanism of action

What this will not teach youWhat this will not teach you

Will not review specific algorithms (i.e.-Will not review specific algorithms (i.e.-sepsis, low cardiac output syndrome, sepsis, low cardiac output syndrome, anaphylaxis, etc) in detailanaphylaxis, etc) in detail

Developmental PhysiologyDevelopmental Physiology

Myocardial ContractionMyocardial Contraction

Contractility increases over 1Contractility increases over 1stst months of months of life along with:life along with: #’s of sympathetic nerve fibers within #’s of sympathetic nerve fibers within

myocardiummyocardium Total concentration of endogenous Total concentration of endogenous

norepinephrinenorepinephrine

There is a greater dependence of CO on There is a greater dependence of CO on HR than contractility during this timeHR than contractility during this time

Immature HeartImmature Heart

Limited responsiveness to medicationsLimited responsiveness to medications noncontractile contentnoncontractile content availability of releasable NEavailability of releasable NE Less mature sympathetic systemLess mature sympathetic system Underdeveloped intracellular calcium Underdeveloped intracellular calcium

regulatory mechanismsregulatory mechanisms functional reserve capacityfunctional reserve capacity

Ionized CalciumIonized Calcium

Plays central role in maintaining Plays central role in maintaining myocardial contractilitymyocardial contractility Effects mediated via intracellular Effects mediated via intracellular

concentration, calcium requirements of the concentration, calcium requirements of the muscle cell, sensitivity of the myofilaments to muscle cell, sensitivity of the myofilaments to calciumcalcium

1

Vascular Smooth MuscleVascular Smooth Muscle

Calcium dependent effectsCalcium dependent effects Agents that increase intracellular cAMP Agents that increase intracellular cAMP

increase intracellular calcium requirements for increase intracellular calcium requirements for contraction, thus encouraging smooth muscle contraction, thus encouraging smooth muscle relaxation and vasodilationrelaxation and vasodilation

Vascular Smooth MuscleVascular Smooth Muscle

Calcium independent effectsCalcium independent effects G protein mediated activation of G protein mediated activation of

phospholipase C results in breakdown of phospholipase C results in breakdown of phosphatidylinositol bisphosphate into IPphosphatidylinositol bisphosphate into IP33 and and DAG.DAG.

IPIP3 3 releases calcium from the sarcoplasmic releases calcium from the sarcoplasmic reticulum initiating contraction and DAG reticulum initiating contraction and DAG activates protein kinase C with activates protein kinase C with phosphorylation of intracellular proteinsphosphorylation of intracellular proteins

Effects of AgentsEffects of Agents

PressorsPressors: increase systemic vascular resistance : increase systemic vascular resistance and increase blood pressureand increase blood pressure

InotropesInotropes: affect myocardial contractility and : affect myocardial contractility and enhance stroke volumeenhance stroke volume

ChronotropicChronotropic Agents: affect heart rate Agents: affect heart rate

LusotropicLusotropic Agents: improve relaxation during Agents: improve relaxation during diastole and decrease EDP in the ventriclesdiastole and decrease EDP in the ventricles

DromotropicDromotropic Agents: Affects conduction speed Agents: Affects conduction speed through AV node; increases heart ratethrough AV node; increases heart rate

BathmotropicBathmotropic Agents: affect degree of excitability Agents: affect degree of excitability

Alpha-Adrenergic AgentsAlpha-Adrenergic Agents

AlphaAlpha11-adrenergic effects:-adrenergic effects:

Vascular smooth muscle contractionVascular smooth muscle contraction

AlphaAlpha22-adrenergic effects:-adrenergic effects:

Vascular smooth muscle relaxationVascular smooth muscle relaxation

Beta-Adrenergic AgentsBeta-Adrenergic Agents

BetaBeta11-adrenergic effects:-adrenergic effects: Direct cardiac effectsDirect cardiac effects

Inotropy (improved cardiac contractility)Inotropy (improved cardiac contractility)

Chronotropy (increased heart rate)Chronotropy (increased heart rate)

BetaBeta22-adrenergic effects:-adrenergic effects:

VasodilationVasodilation

BronchodilationBronchodilation

Dopaminergic AgentsDopaminergic Agents

Dopaminergic AgentsDopaminergic Agents Several types of receptors located throughout Several types of receptors located throughout

body (Dbody (D11-D-D55))

Certain (esp. DCertain (esp. D1-like1-like & D & D2-like2-like) dopaminergic ) dopaminergic

receptors increase renal and mesenteric receptors increase renal and mesenteric blood flowblood flow

CatecholaminesCatecholamines

Sympathomimetic amines that contain O-Sympathomimetic amines that contain O-dihydrobenzenedihydrobenzene

Dopamine, epinephrine and norepinephrine are Dopamine, epinephrine and norepinephrine are endogenousendogenous

Dobutamine and isoproterenol are syntheticDobutamine and isoproterenol are synthetic

Sustained use or antecedent CHF can lead to Sustained use or antecedent CHF can lead to down-regulation of β-receptors and decrease down-regulation of β-receptors and decrease efficacyefficacy

EpinephrineEpinephrine

Both an alpha- and beta-adrenergic agent Both an alpha- and beta-adrenergic agent 0.01 mcg/kg/min-0.3 mcg/kg/min0.01 mcg/kg/min-0.3 mcg/kg/min Low-dose infusion = β activationLow-dose infusion = β activation

Increase HR, contractility, decrease SVRIncrease HR, contractility, decrease SVR Higher doses = Higher doses = activation activation

Increased SVR and MAPIncreased SVR and MAP

Increased myocardial O2 demandIncreased myocardial O2 demand

EPINEPHRINEEPINEPHRINE

α1 predominantlyVasoconstriction↓ Renal BF↓ Splanchnic BF ↑ Glucose

β1 predominantly↑HR↓ Duration of Systole ↑ Myocardial contractPeriph. arteriolar dil.↑/ ↓ 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)

EpinephrineEpinephrine

Indications for its use as a continuous infusion Indications for its use as a continuous infusion are:are: low cardiac output statelow cardiac output state

beta effects will improve cardiac functionbeta effects will improve cardiac function

alpha effects may increase afterload and decrease alpha effects may increase afterload and decrease cardiac outputcardiac output

septic shockseptic shockuseful for both inotropy and vasoconstrictionuseful for both inotropy and vasoconstriction

EpinephrineEpinephrine

Adverse effects include:Adverse effects include: Anxiety, tremors,palpitationsAnxiety, tremors,palpitations Tachycardia and tachyarrhythmiasTachycardia and tachyarrhythmias Increased myocardial oxygen requirements Increased myocardial oxygen requirements

and potential to cause ischemiaand potential to cause ischemia Decreased splanchnic and hepatic Decreased splanchnic and hepatic

circulation (elevation of AST and ALT)circulation (elevation of AST and ALT) Anti-Insulin effects: lactic acidosis, Anti-Insulin effects: lactic acidosis,

hyperglycemiahyperglycemia

NorepinephrineNorepinephrine

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

NorepinephrineNorepinephrine

Differs from epinephrine in that the Differs from epinephrine in that the vasoconstriction outweighs any increase in vasoconstriction outweighs any increase in cardiac output.cardiac output. i.e. norepinephrine usually increases blood i.e. norepinephrine usually increases blood

pressure and SVR, often without increasing pressure and SVR, often without increasing cardiac output.cardiac output.

NorepinephrineNorepinephrine

Adverse Effects:Adverse Effects: Similar to those of EpinephrineSimilar to those of Epinephrine Can compromise perfusion in extremities and Can compromise perfusion in extremities and

may need to be combined with a vasodilator may need to be combined with a vasodilator e.g. Dobutamine or Nipridee.g. Dobutamine or Nipride

More profound effect on splanchnic circulation More profound effect on splanchnic circulation and myocardial oxygen consumptionand myocardial oxygen consumption

VasopressinVasopressin

a peptide hormone released by the a peptide hormone released by the posterior pituitary in response to rising posterior pituitary in response to rising plasma tonicity or falling blood pressureplasma tonicity or falling blood pressure

possesses antidiuretic and vasopressor possesses antidiuretic and vasopressor propertiesproperties

deficiency of this hormone results in deficiency of this hormone results in diabetes insipidusdiabetes insipidus

VasopressinVasopressin

VasopressinVasopressin

AdministrationAdministration intravenous, intramuscular, or intranasal intravenous, intramuscular, or intranasal

routes routes IV is route for vasopressor activityIV is route for vasopressor activity The half-life of circulating ADH is The half-life of circulating ADH is

approximately 20 minutes, with renal and approximately 20 minutes, with renal and hepatic catabolism via reduction of the hepatic catabolism via reduction of the disulfide bond and peptide cleavage disulfide bond and peptide cleavage

VasopressinVasopressin

AdministrationAdministration interacts with two types of receptorsinteracts with two types of receptors

V1 receptors are found on vascular smooth muscle cells and V1 receptors are found on vascular smooth muscle cells and mediate vasoconstriction mediate vasoconstriction

V2 receptors are found on renal tubule cells and mediate V2 receptors are found on renal tubule cells and mediate antidiuresis through increased water permeability and water antidiuresis through increased water permeability and water resorption in the collecting tubules resorption in the collecting tubules

Newer drug to ACLS for resuscitationNewer drug to ACLS for resuscitation

Use in refractory septic shock with low SVRI in Use in refractory septic shock with low SVRI in pediatrics?pediatrics?

DopamineDopamine

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

DopamineDopamine

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

Dose Dependent effect of Dose Dependent effect of DopamineDopamine

<5 mcg <5 mcg 5 - 10 mcg5 - 10 mcg > 10 mcg> 10 mcg

↑Contractility

Minimal change inHR and SVR

↑ Renal BF

↑ Splanchnic BF

Modest ↑ CO

↑ Renal BF

↓Proximal Tub. Na Absorbtion

↑ Splanchnic BF

↑ HR,

Vasoconstriction

↑/ ↓ Renal BF

↓/↑ Splanchnic BF

DobutamineDobutamine

Synthetic catecholamine with Synthetic catecholamine with 1 1 inotropic effect inotropic effect

(increases stroke volume) and (increases stroke volume) and 2 2 peripheral peripheral

vasodilation (decreases afterload)vasodilation (decreases afterload)

Positive chronotropic effect Positive chronotropic effect 1 1 (increases HR)(increases HR)

Some lusotropic effect Some lusotropic effect

Overall, improves Cardiac Output by above Overall, improves Cardiac Output by above beta-agonist acitivitybeta-agonist acitivity

DobutamineDobutamine

Major metabolite is 3-Major metabolite is 3-OO--methyldobutamine, a potent inhibitor of methyldobutamine, a potent inhibitor of alpha-adrenoceptors.alpha-adrenoceptors. Therefore, vasodilation is possible secondary Therefore, vasodilation is possible secondary

to this metabolite.to this metabolite.

Usual starting infusion rate is Usual starting infusion rate is 5 mcg/kg/min, with the dose being titrated 5 mcg/kg/min, with the dose being titrated to effect up to 20 mcg/kg/min.to effect up to 20 mcg/kg/min.

DOBUTAMINEDOBUTAMINE

D- isomer

Stimulates β1 and β2

L- isomer

Stimulates α1

Dobutamine

DobutamineDobutamine

Used in low C.O. states and CHF e.g. Used in low C.O. states and CHF e.g. myocarditis, cardiomyopathy, myocardial myocarditis, cardiomyopathy, myocardial infarctioninfarction

If BP adequate, can be combined with afterload If BP adequate, can be combined with afterload reducer (Nipride or ACE inhibitor)reducer (Nipride or ACE inhibitor)

In combination with Epi/Norepi in profound In combination with Epi/Norepi in profound shock states to improve Cardiac Output and shock states to improve Cardiac Output and provide some peripheral vasodilatationprovide some peripheral vasodilatation

IsoproterenolIsoproterenol

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

IsoproterenolIsoproterenol

Occasionally used to maintain heart rate Occasionally used to maintain heart rate following heart transplantation.following heart transplantation.

Dose starts at 0.01 mcg/kg/min and is Dose starts at 0.01 mcg/kg/min and is increased to 2.0 mcg/kg/min for desired increased to 2.0 mcg/kg/min for desired effect.effect.

Avoid in patients with subaortic Avoid in patients with subaortic stenosis, and hypertrophic stenosis, and hypertrophic cardiomyopathy or TOF lesions cardiomyopathy or TOF lesions because increases the outflow gradientbecause increases the outflow gradient

Milrinone/AmrinoneMilrinone/Amrinone

Belong to class of agents “Bipyridines”Belong to class of agents “Bipyridines”Non-receptor mediated activity based on selective Non-receptor mediated activity based on selective inhibition of Phosphodiesterase Type III enzyme inhibition of Phosphodiesterase Type III enzyme resulting in cAMP accumulation in myocardiumresulting in cAMP accumulation in myocardiumcAMP increases force of contraction and rate and cAMP increases force of contraction and rate and extent of relaxation of myocardiumextent of relaxation of myocardiumInotropic, vasodilator and lusotropic effectInotropic, vasodilator and lusotropic effectAdvantage over catecholamines: Advantage over catecholamines: Independent action from Independent action from -receptor activation, -receptor activation,

particularly when these receptors are downregulated particularly when these receptors are downregulated (CHF and chronic catecholamine use)(CHF and chronic catecholamine use)

MilrinoneMilrinone

Increases CO by improving contractility, decreased Increases CO by improving contractility, decreased SVR, PVR, lusotropic effect; decreased preload SVR, PVR, lusotropic effect; decreased preload due to vasodilatation due to vasodilatation

Unique in beneficial effects on RV functionUnique in beneficial effects on RV function

Protein binding: 70%Protein binding: 70%

Half-life is 1-4 hoursHalf-life is 1-4 hours

Elimination: primarily renally excretedElimination: primarily renally excreted

Load with 50 mcg/kg over 30 mins followed by Load with 50 mcg/kg over 30 mins followed by 0.25 to 0.75 mcg/kg/min0.25 to 0.75 mcg/kg/min

No increase in myocardial O2 requirementNo increase in myocardial O2 requirement

PDE InhibitionPDE Inhibition

AminophyllineAminophylline MilrinoneMilrinone SildenefilSildenefil

PDE PDE 3 PDE 5

MilrinoneMilrinone

Minimal ↑ HR

↑ CO

Minimal ↑ in O2 demand ↓ SVR

↓ PVR

Diastolic Relaxation

Other Vasoactive AgentsOther Vasoactive Agents

NESRITIDENESRITIDE

Recombinant hBNPRecombinant hBNPSecreted by ventricles in response to Secreted by ventricles in response to ↑ ↑ wall stress and volume overloadwall stress and volume overloadVenous and arteriolar dilator, acts on Venous and arteriolar dilator, acts on Guanylate cyclaseGuanylate cyclaseIt reduces RA pressure, PCWP and It reduces RA pressure, PCWP and cardiac indexcardiac indexDose: Infusion 0.01- 0.03 mcg/kg/minDose: Infusion 0.01- 0.03 mcg/kg/minHypotensionHypotension

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

VasodilatorsVasodilators

Classified by site of actionClassified by site of action

Venodilators: reduce preload - NitroglycerinVenodilators: reduce preload - Nitroglycerin

Arteriolar dilators: reduce afterload Minoxidil and Arteriolar dilators: reduce afterload Minoxidil and HydralazineHydralazine

Combined: act on both arterial and venous beds Combined: act on both arterial and venous beds and reduce both pre- and afterload Sodium and reduce both pre- and afterload Sodium Nitroprusside (Nipride)Nitroprusside (Nipride)

NitroprussideNitroprusside

Vasodilator that acts directly on arterial and Vasodilator that acts directly on arterial and venous vascular smooth muscle.venous vascular smooth muscle.

Indicated in hypertension and low cardiac output Indicated in hypertension and low cardiac output states with increased SVR.states with increased SVR.

Also used in post-operative cardiac surgery to Also used in post-operative cardiac surgery to decrease afterload on an injured heart.decrease afterload on an injured heart.

Action is immediate; half-life is short; titratable Action is immediate; half-life is short; titratable action.action.

NitroprussideNitroprusside

Toxicity is with cyanide, one of the metabolites Toxicity is with cyanide, one of the metabolites of the breakdown of nipride.of the breakdown of nipride.

Severe, unexplained metabolic acidosis might Severe, unexplained metabolic acidosis might suggest cyanide toxicity.suggest cyanide toxicity.

Dose starts at 0.5 mcg/kg/min and titrate to 5 Dose starts at 0.5 mcg/kg/min and titrate to 5 mcg/kg/min to desired effect. May go higher (up mcg/kg/min to desired effect. May go higher (up to 10 mcg/kg/min) for short periods of time.to 10 mcg/kg/min) for short periods of time.

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

NitroglycerineNitroglycerine

Used to improve myocardial perfusion Used to improve myocardial perfusion following cardiac surgeryfollowing cardiac surgery

Dose ranges from 0.5 to 8 mcg/kg/min. Dose ranges from 0.5 to 8 mcg/kg/min. Typical dose is 2 mcg/kg/min for 24 to 48 Typical dose is 2 mcg/kg/min for 24 to 48 hours post-operativelyhours post-operatively

Methemoglobinemia is potential side effectMethemoglobinemia is potential side effect

SummarySummary

Relative receptor activity of most Relative receptor activity of most commonly used inotropescommonly used inotropes

α1 α2 β1 β2 DA

Norepinephrine +++ +++ + - -

Epinephrine +++ ++ +++ ++ -

Dopamine ++ + ++ +++ +++

Dobutamine + - +++ + -

Isoproterenol - - ++ ++ -

Receptor Activity (continued)Receptor Activity (continued)