intensive care cardiovascular pharmacology

Toni Petrillo-Albarano, MDDirector, Pediatric Transport

Division of Critical Care Medicine

"F igh t o r F lig h t "

S ym pa the tic

"S no o ze an d L o ose"

P a ra sym pa the tic

A u to n om ic S ys tem S o m a tic S ys tem

P e rip he ra l N e rv ou s system C e ntra l N erv ou s S ys tem

N e rvo us S ys tem

Catecholamines Naturally occurring, biologically active

amines Sympathomimetic

Mimics stimulation of the sympathetic nervous system

Adrenergic Refers to the sympathetic nervous system

Cholinergic Refers to the parasympathetic nervous

system Dopaminergic

Dopamine receptors in renal, visceral, coronary, and cerebral areas

Inotropic Influencing the force of contraction

Chronotropic Influencing the rate of contraction

Six receptor subtypes: alpha 1 (post-synaptic)

alpha 2 (pre-synaptic)

beta 1 (cardiac)

beta 2 (vascular/bronchial smooth muscle)

DA 1 (post-synaptic)

DA 2 (pre-synaptic)

ALPHA 1: Vasoconstriction Mydriasis Uterine contraction Bladder contraction Insulin inhibition Glucagon inhibition

ALPHA 2: Inhibition of

norepinephrine release

BETA 1: Inotropy Chronotropy Lipolysis

BETA 2: Vasodilation Bronchodilation Uterine relaxation Bladder relaxation Insulin release Glucagon release

Desensitization: 2o to Chronic exposure

Mechanisms Uncoupling Down-regulation Sequestration

BaroreceptorsBaroreceptors

Peripheral Peripheral vascular vascular resistanceresistance

Parasympathetic Parasympathetic autonomic autonomic

nervous nervous systemsystem

Heart Heart raterate

VASOMOTOR CENTERVASOMOTOR CENTER

Sympathetic Sympathetic autonomic autonomic

nervous nervous systemsystem

Contractile Contractile forceforce

Venous Venous tonetone

Blood Blood volumevolume

VenousVenousreturnreturn

StrokeStrokevolumevolume

CardiacCardiac outputoutput

Meanarterial

pressure

Renal blood Renal blood flow/pressureflow/pressure

ReninRenin AngiotensinAngiotensinAldosteroneAldosterone

Hor

mon

al

feed

bac

k lo

opA

uto

nom

ic

feed

bac

k lo

op

C.O.=Heart Rate x Stroke Volume Heart rate Stroke volume:

Preload- volume of blood in ventricle Afterload- resistance to contraction Contractility- force applied

PreloadPreloadAfterloadAfterloadContractiliContractilityty

ResistancResistancee

Cardiac Cardiac OutputOutput

Stroke Stroke VolumeVolume

Heart RateHeart Rate

Arterial Arterial PressurePressure

OO22 Delivery Delivery

OO22 Content Content

x

Inadequate tissue perfusion to meet the tissue demands a result of inadequate blood flow and/or

inadequate oxygen delivery.

Fluid

Pump

Vessels

Flow

H ig h o rN o r m a lF u n c tio n

M ald is tr ib u tedB lood F low

D ecreased S V R

C om p en sa ted

D em in ish edT issue

P erfu s ion

L owC ard iacO u tp ut

R ed u cedS y sto lic F in c t ion

U n com p en sa ted

M y ocard ia lD y sfun ct ion

M y ocard ia lD am age

R ed u cedV en tr icu lar

F illin g

P er icard ia lT am p on ade

R ed u cedP re load

H em m orrh age

Septic (Distributive) Cardiogenic Obstructive Hypovolemic

SHOCKSHOCK

Inadequate Fluid Volume (decreased preload) Fluid depletion

internal external

Hemorrhage internal external

Pump Malfunction (decreased contractility) Electrical Failure Mechanical Failure

cardiomyopathy metabolic anatomic hypoxia/ischemia

Abnormal Vessel Tone (decreased afterload) Sepsis Anaphylaxis Neurogenesis (spinal) Drug intoxication (TCA, calcium channel

blocker)

OBSTRUCTED FLOW

Pericardial tamponade

Pulmonary embolism

Pulmonary hypertension

Type of Shock

Preload

Afterload

Contractility

Cardiac Output

Cardiogenic

Hypovolemic

Septic

Early

Late

Obstructive

Distributive

DopamineDopamine

EpinephrineEpinephrineNorepinephrine

Norepinephrine Dobutamine

Dobutamine

Isopro

ternol

Isopro

ternol

Neosynephrine

Neosynephrine

ßß

Usage: activates multiple receptors

DA1, DA2, beta, alpha

receptors activated in dose related manner

shown to increase at low doses: glomerular filtration rate renal plasma flow urinary Na+ excretion

Pharmacodynamics: 0.5 - 2.0 mcg/kg/min - dopaminergic 2.0 - 5.0 mcg/kg/min - beta 1 5.0 - 20 mcg/kg/min - alpha

Indications: Low cardiac output Hypotension with SVR Risk of renal ischemia

In healthy humans and animal models, RDD augments: RBF, GFR, and natriuresis

In experimental models of ischemia and nephrotoxic ARF, RDD augments: RBF, GFR, and natriuresis

Denton et al, Kidney Int. 49:4-14,1996Denton et al, Kidney Int. 49:4-14,1996

Most human studies failed to demonstrate: RDD prevents ARF in high risk patients improves renal function or effects outcome in

established ARF The “dark side”

cardiovascular and metabolic complications

Denton et al, Kidney Int. 49:4-14,1996Denton et al, Kidney Int. 49:4-14,1996

Complications: activity with NE depletion PA pressure pulmonary vascular resistance Dysrhythmias Renal vasoconstriction Tissue necrosis

Is Dopamine the Devil?

Dopamine administration can reduce the release of a number of hormones from the anterior pituitary gland, including prolactin which can have important immunoprotective effects

Dopamine administration was associated with ICU and hospital mortality rates 20% higher than in patients with shock who did not receive dopamine

Critical Care Medicine - Volume 34, Issue 3 (March 2006)

Synthetic catecholamine Direct beta1 weak alpha Indications:

Low cardiac output in patients at risk for: Myocardial ischemia Pulmonary hypertension LV dysfunction (cardiomyopathy)

Dosemcg/kg/min

0.5-2.5 5 7.5-10

Receptor beta 1 beta 1 beta 1

MajorEffects

VariablyCI (15%)

CI (15%) BP (5%)HR (no change)SVRPVR

CI (30%) BP (15%) HR (5%)SVRPVR

Major indication bradycardia

Pure beta Potent pulmonary/ bronchial vasodilator Increased cardiac output Widened pulse pressure Increased flow to non-critical tissue beds

(skeletal muscle)

Tachycardia Dysrhythmias Peripheral vasodilation Increased myocardial consumption

CPK indicating myocardial necrosis Decreased coronary O2 delivery “Splanchnic steal” by skeletal muscle

Pressor of choice post-arrest Shock

with bradycardia unresponsiveness to other

vasopressors anaphylaxis

Low cardiac output syndrome

Limited data available in children Plasma concentration varies linearly with

infusion rate Clearance

15.6-79.2 m/kg/min

Most potent catecholamine Direct acting

no catecholamine stores needed Prominent alpha and beta

effects Increased diastolic pressures

Dosemcg/kg/min

0.02-0.08 0.2-0.8 0.8-2.0 >2.0

Population Adultspost CVsurgery

Newbornanimals

Newbornanimals

Newbornanimals

Receptor beta1,beta2

beta1,beta2

beta1, alpha1 alpha1

Majoreffects

CI HR BP SVR PVR

CI HR BP SVR PVR

CI SVR PVR

Complications Renal ischemia Dysrhythmias Severe hypertension Myocardial necrosis Hyperglycemia Hypokalemia

Leave ‘em Dead!Leave ‘em Dead!

Indications Sepsis with vasodilation unresponsive

to volume expansion Hypotension unresponsive to therapy

Dose: 0.05 - 1 mcg/kg/min

t 1/2 = 2 - 2.5 min

Potent peripheral alpha agonist Little beta 1 effects

Minimal to no beta 2

Produces vasoconstriction SVR, PVR increases systolic, MAP, diastolic BP

Renal vasoconstriction may be decreased with dopamine

Possible cardiac function due to increased afterload

Dysrhythmias Tissue necrosis

Mechanism of action Phosphodiesterase III inhibitor

Pharmacodynamics: Almost pure inotrope

CI Potent vasodilator

SVR PVR

Bolus: 50 mcg/kg Infusion: 0.375 - 0.75 mcg/kg/min

Pharmacokinetics: t 1/2 = 90 min

Side effects: Hypotension Thrombocytopenia

Advantages: No precipitation Short t 1/2

ADH Analog Increases cyclic adenosine monophosphate (cAMP)

which increases water permeability at the renal tubule resulting in decreased urine volume and increased osmolality

direct vasoconstrictor (primarily of capillaries and small arterioles) through the V1 vascular receptors

directly stimulates receptors in pituitary gland resulting in increased ACTH production; may restore catecholamine sensitivity

Vasodilatory shock with hypotension unresponsive to fluid resuscitation and exogenous catecholamines 0.0003-0.002 units/kg/minute (0.018-0.12

units/kg/hour); titrate to effect

A Rational Approach to Pressor A Rational Approach to Pressor Use in the PICUUse in the PICU

Shock / HypotensionShock / Hypotension

Volume ResuscitationVolume Resuscitation

Signs of adequate circulationSigns of adequate circulation

Adequate MAPAdequate MAP

NONO

NO NO pressorspressors

YesYes

A Rational Approach to Pressor A Rational Approach to Pressor Use in the PICUUse in the PICU

NONO

Dopamine?? Or Dopamine?? Or perhaps now NEperhaps now NE

Inadequate MAPInadequate MAP

NorepiNorepi

Signs of adequate circulationSigns of adequate circulation

Adequate MAPAdequate MAP

A Rational Approach to Pressor A Rational Approach to Pressor Use in the PICUUse in the PICU

norepinephrinenorepinephrine

Inadequate MAPInadequate MAP

low C.O.low C.O.

epinephrineepinephrine

adequate adequate MAPMAP

Milrinone or Milrinone or dobutaminedobutamine

Good C.OGood C.O

VasopressinVasopressin

COCO

Questions ???Questions ???