Toni petrillo albarano md director pediatric transport division of critical care medicine
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Toni Petrillo-Albarano, MD Director, Pediatric Transport Division of Critical Care Medicine. Intensive Care Cardiovascular Pharmacology. Catecholamines Naturally occurring, biologically active amines Sympathomimetic Mimics stimulation of the sympathetic nervous system.

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Intensive Care Cardiovascular Pharmacology

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Toni petrillo albarano md director pediatric transport division of critical care medicine

Toni Petrillo-Albarano, MD

Director, Pediatric Transport

Division of Critical Care Medicine

Intensive CareCardiovascular Pharmacology


Cardiovascular pharmacology terminology review

  • Catecholamines

    • Naturally occurring, biologically active amines

  • Sympathomimetic

    • Mimics stimulation of the sympathetic nervous system

Cardiovascular PharmacologyTerminology Review


Cardiovascular pharmacology terminology review1

  • Adrenergic

    • Refers to the sympathetic nervous system

  • Cholinergic

    • Refers to the parasympathetic nervous system

  • Dopaminergic

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

Cardiovascular PharmacologyTerminology Review


Cardiovascular pharmacology terminology review2

  • Inotropic

    • Influencing the force of contraction

  • Chronotropic

    • Influencing the rate of contraction

Cardiovascular PharmacologyTerminology Review


Cardiovascular pharmacology adrenoreceptors

  • Six receptor subtypes:

    • alpha 1 (post-synaptic)

    • alpha 2 (pre-synaptic)

    • beta 1 (cardiac)

    • beta2 (vascular/bronchial smooth muscle)

    • DA 1 (post-synaptic)

    • DA 2 (pre-synaptic)

Cardiovascular PharmacologyAdrenoreceptors


Cardiovascular pharmacology adrenoreceptors1

Cardiovascular PharmacologyAdrenoreceptors

  • ALPHA 1:

    • Vasoconstriction

    • Mydriasis

    • Uterine contraction

    • Bladder contraction

    • Insulin inhibition

    • Glucagon inhibition

  • ALPHA 2:

    • Inhibition of norepinephrine release


Cardiovascular pharmacology adrenoreceptors2

Cardiovascular PharmacologyAdrenoreceptors

  • BETA 1:

    • Inotropy

    • Chronotropy

    • Lipolysis

  • BETA 2:

    • Vasodilation

    • Bronchodilation

    • Uterine relaxation

    • Bladder relaxation

    • Insulin release

    • Glucagon release


Cardiovascular pharmacology adrenoreceptors3

  • Desensitization:

    • 2o to Chronic exposure

  • Mechanisms

    • Uncoupling

    • Down-regulation

    • Sequestration

Cardiovascular PharmacologyAdrenoreceptors


Intensive care cardiovascular pharmacology

VASOMOTOR CENTER

Sympathetic

autonomic

nervous

system

Parasympathetic

autonomic

nervous

system

Autonomic

feedback loop

Baroreceptors

Peripheral

vascular

resistance

Contractile

force

Venous

tone

Heart

rate

Mean

arterial

pressure

Cardiac

output

Venous

return

Stroke

volume

Blood

volume

Hormonal

feedback loop

Aldosterone

Renal blood

flow/pressure

Renin

Angiotensin


Cardiac output

Cardiac Output

  • C.O.=Heart Rate x Stroke Volume

  • Heart rate

  • Stroke volume:

    • Preload- volume of blood in ventricle

    • Afterload- resistance to contraction

    • Contractility- force applied


Intensive care cardiovascular pharmacology

Preload

Afterload

Contractility

x

Stroke Volume

Heart Rate

O2 Content

Cardiac Output

Resistance

O2 Delivery

Arterial Pressure


Intensive care cardiovascular pharmacology

  • Inadequate tissue perfusion to meet the tissue demands

    • a result of inadequate blood flow and/or inadequate oxygen delivery.


Mechanical requirements for adequate tissue perfusion

Fluid

Pump

Vessels

Flow

Mechanical Requirements for Adequate Tissue Perfusion


Physiology of shock

Septic

(Distributive)

Cardiogenic

Obstructive

Hypovolemic

Physiology of Shock

SHOCK


Hypovolemic shock

  • Inadequate Fluid Volume (decreased preload)

    • Fluid depletion

      • internal

      • external

    • Hemorrhage

      • internal

      • external

Hypovolemic Shock:


Cardiogenic shock

  • Pump Malfunction (decreased contractility)

    • Electrical Failure

    • Mechanical Failure

      • cardiomyopathy

      • metabolic

      • anatomic

      • hypoxia/ischemia

Cardiogenic Shock:


Distributive shock

  • Abnormal Vessel Tone (decreased afterload)

    • Sepsis

    • Anaphylaxis

    • Neurogenesis (spinal)

    • Drug intoxication (TCA, calcium channel blocker)

Distributive Shock


Obstructive shock

  • OBSTRUCTED FLOW

    • Pericardial tamponade

    • Pulmonary embolism

    • Pulmonary hypertension

OBSTRUCTIVE SHOCK


Hemodynamic assessment of shock

Hemodynamic Assessment of Shock


Alpha beta meter



ß

Dopamine

Epinephrine

Dobutamine

Norepinephrine

Alpha-Beta Meter

Neosynephrine

Isoproternol


Cardiovascular pharmacology dopamine

  • 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

Cardiovascular PharmacologyDopamine


Cardiovascular pharmacology dopamine1

  • 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

Cardiovascular PharmacologyDopamine


Cardiovascular pharmacology dopamine2

  • Indications:

    • Low cardiac output

    • Hypotension with SVR

    • Risk of renal ischemia

Cardiovascular PharmacologyDopamine


Renal dose dopamine rdd fact or fiction summary of the data

  • 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

Renal Dose Dopamine (RDD)Fact or Fiction?Summary of the Data

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


Renal dose dopamine rdd fact or fiction summary of the data1

  • 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

Renal Dose Dopamine (RDD)Fact or Fiction?Summary of the Data

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


Cardiovascular pharmacology dopamine3

  • Complications:

    • activity with NE depletion

    • PA pressure

    • pulmonary vascular resistance

    • Dysrhythmias

    • Renal vasoconstriction

    • Tissue necrosis

Cardiovascular PharmacologyDopamine


Is dopamine the devil

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)


Cardiovascular pharmacology dobutamine

  • Synthetic catecholamine

  • Direct beta1 weak alpha

  • Indications:

    • Low cardiac output in patients at risk for:

      • Myocardial ischemia

      • Pulmonary hypertension

      • LV dysfunction (cardiomyopathy)

Cardiovascular PharmacologyDobutamine


Dobutamine pharmacodynamics

DobutaminePharmacodynamics


Isoproterenol isuprel

  • Major indication

    • bradycardia

  • Pure beta

  • Potent pulmonary/ bronchial vasodilator

  • Increased cardiac output

  • Widened pulse pressure

  • Increased flow to non-critical tissue beds (skeletal muscle)

Isoproterenol (Isuprel)


Isoproterenol isuprel drawbacks

  • Tachycardia

  • Dysrhythmias

  • Peripheral vasodilation

  • Increased myocardial consumption

    • CPK indicating myocardial necrosis

  • Decreased coronary O2 delivery

  • “Splanchnic steal” by skeletal muscle

Isoproterenol (Isuprel) Drawbacks


Epinephrine indications

  • Pressor of choice post-arrest

  • Shock

    • with bradycardia

    • unresponsiveness to other vasopressors

    • anaphylaxis

  • Low cardiac output syndrome

Epinephrine Indications


Epinephrine pharmacokinetics

  • Limited data available in children

  • Plasma concentration varies linearly with infusion rate

  • Clearance

    • 15.6-79.2 m/kg/min

Epinephrine Pharmacokinetics


Epinephrine effects

  • Most potent catecholamine

  • Direct acting

    • no catecholamine stores needed

  • Prominent alpha and beta effects

  • Increased diastolic pressures

Epinephrine Effects


Epinephrine pharmacodynamics

Epinephrine Pharmacodynamics


Epinephrine

  • Complications

    • Renal ischemia

    • Dysrhythmias

    • Severe hypertension

    • Myocardial necrosis

    • Hyperglycemia

    • Hypokalemia

Epinephrine


Norepinephrine levophed

NorepinephrineLevophed

Leave ‘em Dead!


Norepinephrine levophed indications

  • 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

Norepinephrine (Levophed) Indications


Norepinephrine levophed effects

  • Potent peripheral alpha agonist

  • Little beta 1 effects

  • Minimal to no beta 2

  • Produces

    • vasoconstriction

    • SVR, PVR

    • increases systolic, MAP, diastolic BP

Norepinephrine (Levophed) Effects


Norepinephrine levophed complications

  • Renal vasoconstriction

    • may be decreased with dopamine

  • Possible cardiac function due to increased afterload

  • Dysrhythmias

  • Tissue necrosis

Norepinephrine (Levophed) Complications


Milrinone primacor

  • 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

Milrinone (Primacor)


Milrinone primacor1

  • Pharmacokinetics:

    • t 1/2 = 90 min

  • Side effects:

    • Hypotension

    • Thrombocytopenia

  • Advantages:

    • No precipitation

    • Short t 1/2

Milrinone (Primacor)


Vasopressin

  • 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

Vasopressin


Vasopressin1

  • 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

Vasopressin


Intensive care cardiovascular pharmacology

A Rational Approach to Pressor Use in the PICU

Shock / Hypotension

Volume Resuscitation

Signs of adequate circulation

Adequate MAP

NO pressors

Yes

NO


Intensive care cardiovascular pharmacology

A Rational Approach to Pressor Use in the PICU

Signs of adequate circulation

Adequate MAP

NO

Dopamine?? Or perhaps now NE

Inadequate MAP

Norepi


Intensive care cardiovascular pharmacology

A Rational Approach to Pressor Use in the PICU

norepinephrine

adequate MAP

Milrinone or dobutamine

CO

Inadequate MAP

low C.O.

Good C.O

epinephrine

Vasopressin


Intensive care cardiovascular pharmacology

Questions ???


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