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

Intensive CareCardiovascular Pharmacology


  • Catecholamines

    • Naturally occurring, biologically active amines

  • Sympathomimetic

    • Mimics stimulation of the sympathetic nervous system

Cardiovascular PharmacologyTerminology Review


  • 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


  • Inotropic

    • Influencing the force of contraction

  • Chronotropic

    • Influencing the rate of contraction

Cardiovascular PharmacologyTerminology Review


  • 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 PharmacologyAdrenoreceptors

  • ALPHA 1:

    • Vasoconstriction

    • Mydriasis

    • Uterine contraction

    • Bladder contraction

    • Insulin inhibition

    • Glucagon inhibition

  • ALPHA 2:

    • Inhibition of norepinephrine release


Cardiovascular PharmacologyAdrenoreceptors

  • 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

Cardiovascular PharmacologyAdrenoreceptors


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

  • C.O.=Heart Rate x Stroke Volume

  • Heart rate

  • Stroke volume:

    • Preload- volume of blood in ventricle

    • Afterload- resistance to contraction

    • Contractility- force applied


Preload

Afterload

Contractility

x

Stroke Volume

Heart Rate

O2 Content

Cardiac Output

Resistance

O2 Delivery

Arterial Pressure


  • Inadequate tissue perfusion to meet the tissue demands

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


Fluid

Pump

Vessels

Flow

Mechanical Requirements for Adequate Tissue Perfusion


Septic

(Distributive)

Cardiogenic

Obstructive

Hypovolemic

Physiology of Shock

SHOCK


  • Inadequate Fluid Volume (decreased preload)

    • Fluid depletion

      • internal

      • external

    • Hemorrhage

      • internal

      • external

Hypovolemic Shock:


  • Pump Malfunction (decreased contractility)

    • Electrical Failure

    • Mechanical Failure

      • cardiomyopathy

      • metabolic

      • anatomic

      • hypoxia/ischemia

Cardiogenic Shock:


  • Abnormal Vessel Tone (decreased afterload)

    • Sepsis

    • Anaphylaxis

    • Neurogenesis (spinal)

    • Drug intoxication (TCA, calcium channel blocker)

Distributive Shock


  • OBSTRUCTED FLOW

    • Pericardial tamponade

    • Pulmonary embolism

    • Pulmonary hypertension

OBSTRUCTIVE SHOCK


Hemodynamic Assessment of Shock




ß

Dopamine

Epinephrine

Dobutamine

Norepinephrine

Alpha-Beta Meter

Neosynephrine

Isoproternol


  • 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


  • 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


  • Indications:

    • Low cardiac output

    • Hypotension with SVR

    • Risk of renal ischemia

Cardiovascular PharmacologyDopamine


  • 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


  • 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


  • Complications:

    • activity with NE depletion

    • PA pressure

    • pulmonary vascular resistance

    • Dysrhythmias

    • Renal vasoconstriction

    • Tissue necrosis

Cardiovascular PharmacologyDopamine


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)

Cardiovascular PharmacologyDobutamine


DobutaminePharmacodynamics


  • 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)


  • Tachycardia

  • Dysrhythmias

  • Peripheral vasodilation

  • Increased myocardial consumption

    • CPK indicating myocardial necrosis

  • Decreased coronary O2 delivery

  • “Splanchnic steal” by skeletal muscle

Isoproterenol (Isuprel) Drawbacks


  • Pressor of choice post-arrest

  • Shock

    • with bradycardia

    • unresponsiveness to other vasopressors

    • anaphylaxis

  • Low cardiac output syndrome

Epinephrine Indications


  • Limited data available in children

  • Plasma concentration varies linearly with infusion rate

  • Clearance

    • 15.6-79.2 m/kg/min

Epinephrine Pharmacokinetics


  • Most potent catecholamine

  • Direct acting

    • no catecholamine stores needed

  • Prominent alpha and beta effects

  • Increased diastolic pressures

Epinephrine Effects


Epinephrine Pharmacodynamics


  • Complications

    • Renal ischemia

    • Dysrhythmias

    • Severe hypertension

    • Myocardial necrosis

    • Hyperglycemia

    • Hypokalemia

Epinephrine


NorepinephrineLevophed

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

Norepinephrine (Levophed) Indications


  • 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


  • Renal vasoconstriction

    • may be decreased with dopamine

  • Possible cardiac function due to increased afterload

  • Dysrhythmias

  • Tissue necrosis

Norepinephrine (Levophed) Complications


  • 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)


  • Pharmacokinetics:

    • t 1/2 = 90 min

  • Side effects:

    • Hypotension

    • Thrombocytopenia

  • Advantages:

    • No precipitation

    • Short t 1/2

Milrinone (Primacor)


  • 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


  • 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


A Rational Approach to Pressor Use in the PICU

Shock / Hypotension

Volume Resuscitation

Signs of adequate circulation

Adequate MAP

NO pressors

Yes

NO


A Rational Approach to Pressor Use in the PICU

Signs of adequate circulation

Adequate MAP

NO

Dopamine?? Or perhaps now NE

Inadequate MAP

Norepi


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


Questions ???


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