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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 Care Cardiovascular Pharmacology. Catecholamines Naturally occurring, biologically active amines Sympathomimetic Mimics stimulation of the sympathetic nervous system.

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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
slide10

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
slide12

Preload

Afterload

Contractility

x

Stroke Volume

Heart Rate

O2 Content

Cardiac Output

Resistance

O2 Delivery

Arterial Pressure

slide13

Inadequate tissue perfusion to meet the tissue demands

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

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
slide46

A Rational Approach to Pressor Use in the PICU

Shock / Hypotension

Volume Resuscitation

Signs of adequate circulation

Adequate MAP

NO pressors

Yes

NO

slide47

A Rational Approach to Pressor Use in the PICU

Signs of adequate circulation

Adequate MAP

NO

Dopamine?? Or perhaps now NE

Inadequate MAP

Norepi

slide48

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

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