Vasoactive Drugs

Management of ShockRole of Inotropic & Vasoactive drugs

Dr. Waheed A. Radwan

Professor of Critical Care Medicine

Cairo University

Glossary of terms

• Inotropes: agents that improve myocardial contractility and enhance stroke volume

• Pressors: agents that increase systemic vascular resistance and increase blood pressure

• Chronotropic: Increase heart rate

• Lusotropic: improve relaxation during diastole and decrease EDP in the ventricles

CONTRACTILITY HEART RATE

PRELOAD AFTERLOAD

L/Min

CARDIACOUTPUT

(CI=CO/m²)

Determinants of Cardiac Output

CARDIOVASCULAR MEDICATIONS

• From ICU standpoint, can be divided into two main groups:– Cardiac arrest medications– Cardiac medications via continuous infusions

• Many of the meds used during a cardiac arrest may also be given as continuous infusions.

CARDIOVASCULAR MEDICATIONS

• Main actions of most of the following cardiovascular medications will be determined by the adrenergic effects of the medications.

• Can either be:– alpha-adrenergic– beta-adrenergic– dopaminergic

ALPHA-ADRENERGIC MEDICATIONS

• Can be divided into:– Alpha1-adrenergic effects:

• Vascular smooth muscle contraction

– Alpha2-adrenergic effects:• Vascular smooth muscle relaxation--this is a very

mild effect only at low doses of an alpha-adrenergic agent like epinephrine.

BETA-ADRENERGIC MEDICATIONS

• Can be divided into:– Beta1-adrenergic effects:

• Direct cardiac effects

– Inotropy (improved cardiac contractility)

– Chronotropy (increased heart rate)

– Beta2-adrenergic effects:• Vasodilation

• Bronchodilation

CARDIAC MEDS VIA CONTINUOUS INFUSION

• Epinephrine

• Norepinephrine

• Dopamine

• Dobutamine

• Milrinone/Amrinone

• Sodium Nitroprusside

• Nitroglycerin

• Isoproterenol

EPINEPHRINE

• Both an alpha- and beta-adrenergic agent• Therefore, indications for its use as a

continuous infusion are:– low cardiac output state

• beta effects will improve cardiac function• alpha effects may increase afterload and decrease

cardiac output

– septic shock• useful for both inotropy and vasoconstriction

EPINEPHRINE

• Actions are dose dependent (mcg/kg/min):– 0.02-0.08 = mostly beta1 and beta2 stimulation.

• increased cardiac output

• mild vasodilation

– 0.1-2.0 = mix of beta1 and alpha1

• increase cardiac output

• increase SVR = vasoconstriction

– > 2.0 = mostly alpha1

• increase SVR, and may decrease CO by increasing afterload

EPINEPHRINE

• Side effects include:

• Anxiety, tremors,palpitations

• Tachycardia and tachyarrhythmias

• Increased myocardial oxygen requirements and potential to cause ischemia

• Decreased splanchnic and hepatic circulation (elevation of AST and ALT)

• Anti-Insulin effects: lactic acidosis, hyperglycemia

NOREPINEPHRINE

• Employed primarily for its alpha agonist effect - increases SVR (and B.P.) without significantly increasing C.O.

• Used in cases of low SVR and hypotension such as profound “warm shock” with a normal or high C.O. state

• Infusion rates titrated between 0.05 to 1 mcg/kg/min

NOREPINEPHRINE

• In general, norepinephrine differs from epinephrine in that at doses used in clinical practice, the vasoconstriction outweighs any increase in cardiac output.

– i.e. norepinephrine usually increases blood pressure and SVR, often without increasing cardiac output.

NOREPINEPHRINE

• Side Effects:

• Similar to those of Epinephrine

• Can compromise perfusion in extremities and may need to be combined with a vasodilator e.g. Dobutamine or Nipride

• More profound effect on sphlancnic circulation and myocardial oxygen consumption

DOPAMINE

• Intermediate product in the enzymatic pathway leading to the production of norepinephrine; thus, it indirectly acts by releasing norepinephrine.

• Directly has alpha, beta and dopaminergic actions which are dose-dependent.

• Indications are based on the adrenergic actions desired.

DOPAMINE

• Improve renal perfusion 2-5 mcg/kg/min

• Improve C.O. in mild to moderate Cardiogenic or Distributive Shock 5-10mcg/kg/min

• Post-resuscitation stabilization in patients with hypotension (in conjuction with fluid therapy) 10-20mcg/kg/min

DOBUTAMINE

• Synthetic catecholamine with inotropic effect (increases stroke volume) and peripheral vasodilation (decreases afterload)

• Positive chronotropic effect (increases HR)

• Some lusotropic effect

• Overall, improves Cardiac Output by above beta-agonist acitivity

DOBUTAMINE

• Major metabolite is 3-O-methyldobutamine, a potent inhibitor of alpha-adrenoceptors.– Therefore, vasodilation is possible secondary to

this metabolite.

• Usual starting infusion rate is 5 mcg/kg/min, with the dose being titrated to effect up to 20 mcg/kg/min.

DOBUTAMINE

• Used in low C.O. states and CHF e.g. myocarditis, cardiomyopathy, myocardial infarction

• If BP adequate, can be combined with afterload reducer (Nipride or ACE inhibitor)

• In combination with Epi/Norepi in profound shock states to improve Cardiac Output and provide some peripheral vasodilatation

MILRINONE/AMRINONE

• Belong to new class of agents “Bipyridines”

• Non-receptor mediated activity based on selective inhibition of Phosphodiesterase Type III enzyme resulting in cAMP accumulation in myocardium

• cAMP increases force of contraction and rate and extent of relaxation of myocardium

• Inotropic, vasodilator and lusotropic effect

AMRINONE

• First generation agent - limited use now

• Long half-life (4.4 hours) with potential for prolonged hypotension after loading dose

• Associated with thrombocytopenia

• Dosage: Load with 0.75 mg/kg with infusion rate of 5-10 mcg/kg/min

• Milrinone is preferred drug from this group

MILRINONE

• Increases CO by improving contractility, decreased SVR, PVR (?), lusotropic effect; decreased preload due to vasodilatation

• Unique in beneficial effects on RV function

• Half-life is 1-2 hours

• Load with 50 mcg/kg over 30 mins followed by 0.3 to 0.75 mcg/kg/min

• No increase in myocardial O2 requirement

VASODILATORS

• Classified by site of action

• Venodilators: reduce preload - Nitroglycerin

• Arteriolar dilators: reduce afterload Minoxidil and Hydralazine

• Combined: act on both arterial and venous beds and reduce both pre- and afterload Sodium Nitroprusside (Nipride)

NITROPRUSSIDE

• Vasodilator that acts directly on arterial and venous vascular smooth muscle.

• Indicated in hypertension and low cardiac output states with increased SVR.

• Also used in post-operative cardiac surgery to decrease afterload on an injured heart.

• Action is immediate; half-life is short; titratable action.

NITROPRUSSIDE

• Toxicity is with cyanide, one of the metabolites of the breakdown of nipride.

• Severe, unexplained metabolic acidosis might suggest cyanide toxicity.

• Dose starts at 0.5 mcg/kg/min and titrate to 5 mcg/kg/min to desired effect. May go higher (up to 10 mcg/kg/min) for short periods of time.

NITROGLYCERIN• Direct vasodilator as well, but the major

effect is as a venodilator with lesser effect on arterioles.

• Not as effective as nitroprusside in lowering blood pressure.

• Another potential benefit is relaxation of the coronary arteries, thus improving myocardial regional blood flow and myocardial oxygen demand.

NITROGLYCERIN

• Used to improve myocardial perfusion following cardiac surgery

• Dose ranges from 0.5 to 8 mcg/kg/min. Typical dose is 2 mcg/kg/min for 24 to 48 hours post-operatively

• Methemoglobinemia is potential side effect

ISOPROTERENOL

• Synthetic catecholamine

• Non-specific beta agonist with minimal alpha-adrenergic effects.

• Causes inotropy, chronotropy, and systemic and pulmonary vasodilatation.

• Indications: bradycardia, decreased cardiac output, bronchospasm (bronchodilator).

• No longer available in some markets

ISOPROTERENOL

• Occasionally used to maintain heart rate following heart transplantation.

• Dose starts at 0.01 mcg/kg/min and is increased to 1.0 mcg/kg/min for desired effect.

INHALED NITRIC OXIDE

• Selective Pulmonary vasodilator

• Dilates only pulmonary capillaries to alveoli participating in gas exchange

• Decreases intrapulmonary shunt and improves V/Q matching

• Rapidly inactivated by Hgb in pulm. cap. so no systemic side effects (eg hypotension)

INHALED NITRIC OXIDE

• Potential for use in ARDS and Pulmonary Hypertension

• Currently only approved for use in neonatal Pulmonary Hypertension

• Expensive

• Special monitoring equipment required

• Dose: Concentration of 0.5-60 ppm in inhaled gas

Additional considerations

• Mechanical ventilation and oxygen therapy (to conserve CO)

• Analgesia, anxiolysis and sedation

• Electrolyte homeostasis esp Ca and Mg

• Nutrition - avoid hypoglycemia

• Anemia is an “unconstitutional surcharge”

• Last but not the least: Maintain appropriate intravascular volume

Selecting inotropic and vasopressor agents for specific hemodynamic disturbances in children

Hemodynamic pattern Normal Deceased Elevated

Blood pressure or SVR

Septic Shock Stroke index High Stroke Index low to N

None or dopamineDobutamine or dopamine

NorepinephrineDopamine or epinephrine

(or dobutamine plusnorephinephrine)

NoneDobutamine

plusnitroprusside

Cardiogenic shock Dobutamine or amrinoneor dopamine

Epinephrine or dopamine --

Myocardial dysfunction (complicating critical illness)

Dobutamine or dopamineor amrinone

Epinephrine or dopamine(or dobutamine plus

norepinephrine)

Dobutamineplus

nitroprusside

CHF Dobutamine or dopamineor amrinone

-- Dobutamineplus

nitroprusside

Bradycardia None Isoproterenol None

CARDIAC ARREST MEDICATIONS

• Epinephrine

• Atropine

• Sodium Bicarbonate

• Calcium (Chloride or Gluconate)

• Lidocaine

EPINEPHRINE

• Both an alpha- and beta-adrenergic agent

• During cardiac arrest, most think it has the greatest benefit by alpha-adrenergic actions, increasing afterload and thus diastolic blood pressure, leading to improved coronary artery perfusion.

EPINEPHRINE

• Indications:– Cardiac arrest– Severe bronchospasm– Anaphylactic reactions

• Route of Administration– IV or IO– SQ or IM (for bronchospasm)– ET (cardiac arrest without IV or IO access)

EPINEPHRINE

• Dosage:– initial (low) dose: 0.01 mg/kg

= 0.1 cc/kg of 1:10,000

– subsequent (high) doses: 0.1 mg/kg

= (0.1 cc/kg of 1:1,000)

ATROPINE

• Parasympathetic (not an alpha- or beta-adrenergic) agent--acts by blocking cholinergic stimulation of the muscarinic receptors of the heart.

• Results in an increase in the sinus rate of the heart.

• Little effect on systemic vascular resistance or myocardial contractility.

ATROPINE

• Indications:– Bradycardia– Second or third degree heart block– Asystole– Pulseless electrical activity (electrical

mechanical dissociation)

• Route of Administration– IV, IO, ET, SQ, IM, nebulization

ATROPINE

• Dosage:– 10 to 20 mcg/kg– minimum dose is 0.1 mg--smaller doses may

cause reflex bradycardia (central stimulatory effect on the medullary vagal nuclei)

– maximum (adult) dose is 2 mg

SODIUM BICARBONATE

• Use during CPR remains a controversial issue due to lack of evidence showing benefit from receiving bicarbonate.

• Elevates blood pH by binding with hydrogen to form water and CO2

• HCO-3 + H+ => H2CO3 => H2O + CO2

• Must have adequate ventilation to remove CO2 or respiratory acidosis will worsen

SODIUM BICARBONATE

• Adverse effects of acidosis:– Cardiac

• Decrease contractility• Lower threshold for ventricular fibrillation• Decrease responsiveness to catecholamines

– Vascular• Decrease systemic vascular resistance• Decrease systemic vascular responsiveness to

catecholamines• Increase pulmonary vascular resistance

SODIUM BICARBONATE

• Indications:– Pre-existing acidosis– Prolonged CPR (after 10 minutes)– Pulmonary hypertensive crisis– Hyperkalemia

• Route of administration: – IV, IO

• Dosage– 1-2 meq/kg/dose (1 meq/cc or 0.5 meq/cc)

CALCIUM

• Current recommendations for the use of calcium during CPR are restricted to a few specific situations.

• Intracellular calcium plays an important role in the process of cell death, but no studies have shown that transient hypercalcemia worsens outcome after cardiac arrest.

CALCIUM

• Adverse Effects of Hypocalcemia– Decreased myocardial contractility– Decreased systemic vascular resistance– Decreased catecholamine release– Decreased cardiovascular response to

catecholamines

CALCIUM

• Indications:– Hypocalcemia

• Ionized hypocalcemia may result from severe alkalosis or after large transfusions of citrated blood products.

– Hyperkalemia– Hypermagnesemia– Calcium channel blocker overdose

CALCIUM

• Route of administration:– IV, IO only– Calcium chloride--central venous line– Calcium gluconate--peripheral venous line

• Dosage:– Calcium chloride = 10-20 mg/kg– Calcium gluconate = 100-200 mg/kg

LIDOCAINE

• Class 1B antiarrhythmic

• Decreases automaticity threshold and ventricular fibrillation threshold.

• Effective in terminating PVCs.

• Rarely used in pediatric arrests as ventricular tachycardia and ventricular fibrillation are not commonplace.

LIDOCAINE

• Indications:– Ventricular Tachycardia– Ventricular Fibrillation– Frequent PVCs

• Route of Administration:– IV, IO, ET

• Dosage:– 1 mg/kg/dose (may need up to 2.5 mg/kg ET)

ENDOTRACHEAL MEDICATIONS

• LEAN– Lidocaine– Epinephrine– Atropine– Naloxone (Narcan)