Intensive Care Cardiovascular Pharmacology

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Intensive CareCardiovascular Pharmacology

• Toni Petrillo-Albarano, MD
• Director, Pediatric Transport
• Division of Critical Care Medicine

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(No Transcript)
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Cardiovascular PharmacologyTerminology Review

• Catecholamines
• Naturally occurring, biologically active amines
• Sympathomimetic
• Mimics stimulation of the sympathetic nervous
  system

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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

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Cardiovascular PharmacologyTerminology Review

• Inotropic
• Influencing the force of contraction
• Chronotropic
• Influencing the rate of contraction

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Cardiovascular PharmacologyAdrenoreceptors

• 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)

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Cardiovascular PharmacologyAdrenoreceptors

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

• ALPHA 2
• Inhibition of norepinephrine release

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Cardiovascular PharmacologyAdrenoreceptors

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

• BETA 1
• Inotropy
• Chronotropy
• Lipolysis

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Cardiovascular PharmacologyAdrenoreceptors

• Desensitization
• 2o to Chronic exposure
• Mechanisms
• Uncoupling
• Down-regulation
• Sequestration

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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
Venous return
Cardiac output
Blood volume
Stroke volume
Hormonal feedback loop
Aldosterone
Renal blood flow/pressure
Renin
Angiotensin
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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

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Preload Afterload Contractility
x
Stroke Volume
Heart Rate
Cardiac Output
O2 Content
Resistance
Arterial Pressure
O2 Delivery
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• Inadequate tissue perfusion to meet the tissue
  demands
• a result of inadequate blood flow and/or
  inadequate oxygen delivery.

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Mechanical Requirements for Adequate Tissue
Perfusion

• Fluid
• Pump
• Vessels
• Flow

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Physiology of Shock
SHOCK
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Hypovolemic Shock

• Inadequate Fluid Volume (decreased preload)
• Fluid depletion
• internal
• external
• Hemorrhage
• internal
• external

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Cardiogenic Shock

• Pump Malfunction (decreased contractility)
• Electrical Failure
• Mechanical Failure
• cardiomyopathy
• metabolic
• anatomic
• hypoxia/ischemia

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Distributive Shock

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

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OBSTRUCTIVE SHOCK

• OBSTRUCTED FLOW
• Pericardial tamponade
• Pulmonary embolism
• Pulmonary hypertension

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Hemodynamic Assessment of Shock
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Alpha-Beta Meter
? ??
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Dopamine
Epinephrine
Dobutamine
Norepinephrine
Neosynephrine
Isoproternol
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Cardiovascular PharmacologyDopamine

• 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

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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

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Cardiovascular PharmacologyDopamine

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

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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

Denton et al, Kidney Int. 494-14,1996
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Renal Dose Dopamine (RDD)Fact or
Fiction?Summary of the Data

• 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. 494-14,1996
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Cardiovascular PharmacologyDopamine

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

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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)
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Cardiovascular PharmacologyDobutamine

• Synthetic catecholamine
• Direct beta1 weak alpha
• Indications
• Low cardiac output in patients at risk for
• Myocardial ischemia
• Pulmonary hypertension
• LV dysfunction (cardiomyopathy)

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Dobutamine Pharmacodynamics
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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)

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Isoproterenol (Isuprel) Drawbacks

• Tachycardia
• Dysrhythmias
• Peripheral vasodilation
• Increased myocardial consumption
• CPK indicating myocardial necrosis
• Decreased coronary O2 delivery
• Splanchnic steal by skeletal muscle

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Epinephrine Indications

• Pressor of choice post-arrest
• Shock
• with bradycardia
• unresponsiveness to other vasopressors
• anaphylaxis
• Low cardiac output syndrome

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Epinephrine Pharmacokinetics

• Limited data available in children
• Plasma concentration varies linearly with
  infusion rate
• Clearance
• 15.6-79.2 m/kg/min

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Epinephrine Effects

• Most potent catecholamine
• Direct acting
• no catecholamine stores needed
• Prominent alpha and beta effects
• Increased diastolic pressures

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Epinephrine Pharmacodynamics
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Epinephrine

• Complications
• Renal ischemia
• Dysrhythmias
• Severe hypertension
• Myocardial necrosis
• Hyperglycemia
• Hypokalemia

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NorepinephrineLevophed
Leave em Dead!
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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

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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

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Norepinephrine (Levophed) Complications

• Renal vasoconstriction
• may be decreased with dopamine
• Possible cardiac function due to increased
  afterload
• Dysrhythmias
• Tissue necrosis

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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

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Milrinone (Primacor)

• Pharmacokinetics
• t 1/2 90 min
• Side effects
• Hypotension
• Thrombocytopenia
• Advantages
• No precipitation
• Short t 1/2

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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

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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

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A Rational Approach to Pressor
Use in the PICU
Shock / Hypotension
Volume Resuscitation
Signs of adequate circulation Adequate MAP
NO pressors
Yes
NO
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A Rational Approach to Pressor
Use in the PICU
Signs of adequate circulation Adequate MAP
NO
Dopamine?? Or perhaps now NE
Inadequate MAP
Norepi
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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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Questions ???