Post on 02-Jan-2016
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)