Vasopressors and InotropesVasopressors and Inotropes

1/27/101/27/10Jason Begalke, D.O.Jason Begalke, D.O.

Adrenergic Receptor PhysiologyAdrenergic Receptor Physiology

Alpha-1Alpha-1 Beta-1Beta-1 Beta-2Beta-2 DopamineDopamine

Alpha-1 Adrenergic ReceptorsAlpha-1 Adrenergic Receptors

Located in arteriolar wallsLocated in arteriolar walls– Induces significant vasoconstrictionInduces significant vasoconstriction

Present in heartPresent in heart– Slight positive inotropic effect (increased Slight positive inotropic effect (increased

intracellular Ca++).intracellular Ca++).

Beta Adrenergic ReceptorsBeta Adrenergic Receptors

Beta-1 adrenergic receptors are most Beta-1 adrenergic receptors are most common in the heartcommon in the heart– increases in inotropy and chronotropy with increases in inotropy and chronotropy with

minimal vasoconstriction.minimal vasoconstriction. Beta-2 adrenergic receptors in muscle blood Beta-2 adrenergic receptors in muscle blood

vessels induce vasodilation; vessels induce vasodilation; bronchodilation.bronchodilation.

Dopamine ReceptorsDopamine Receptors

Present in the renal, splanchnic, coronary, Present in the renal, splanchnic, coronary, and cerebral vascular beds.and cerebral vascular beds.

Stimulation of these receptors leads to Stimulation of these receptors leads to vasodilation.vasodilation.

Second subtype of dopamine receptors Second subtype of dopamine receptors causes vasoconstriction by inducing causes vasoconstriction by inducing norepinephrine releasenorepinephrine release

Principles Of Use Of Principles Of Use Of Vasopressors and InotropesVasopressors and Inotropes

Hypotension may result from:Hypotension may result from:– HypovolemiaHypovolemia– Pump failurePump failure– Pathologic maldistribution of blood flowPathologic maldistribution of blood flow

Vasopressors are indicated for:Vasopressors are indicated for:– Decrease of >30 mmHg/20% from baseline SBP orDecrease of >30 mmHg/20% from baseline SBP or– MAP <60 mmHg andMAP <60 mmHg and– Evidence of end-organ dysfunction due to Evidence of end-organ dysfunction due to

hypoperfusionhypoperfusion Hypovolemia must be corrected firstHypovolemia must be corrected first

Principles Of Use Of Principles Of Use Of Vasopressors and Inotropes Vasopressors and Inotropes

Use of vasopressors and inotropes is guided Use of vasopressors and inotropes is guided by three fundamental concepts:by three fundamental concepts:– One drug, many receptorsOne drug, many receptors– Dose-response curveDose-response curve– Direct versus reflex actionsDirect versus reflex actions

Volume ResuscitationVolume Resuscitation Repletion of adequate intravascular volume, Repletion of adequate intravascular volume,

when time permits, is crucial prior to the when time permits, is crucial prior to the initiation of vasopressors.initiation of vasopressors.– Vasopressors will be ineffective or only Vasopressors will be ineffective or only

partially effective in the setting of coexisting partially effective in the setting of coexisting hypovolemia.hypovolemia.

Fluids may be withheld in patients with Fluids may be withheld in patients with significant pulmonary edema due to ARDS significant pulmonary edema due to ARDS or CHF.or CHF.

Selection and TitrationSelection and Titration

Choice of an initial agent should be based Choice of an initial agent should be based upon the suspected underlying etiology of upon the suspected underlying etiology of shock.shock.

Dose should be titrated up to achieve Dose should be titrated up to achieve effective BP or end-organ perfusion.effective BP or end-organ perfusion.

If maximal doses of a first agent are If maximal doses of a first agent are inadequate, then a second drug should be inadequate, then a second drug should be added to the first.added to the first.

TachyphylaxisTachyphylaxis

Responsiveness to these drugs can decrease Responsiveness to these drugs can decrease over time due to tachyphylaxis.over time due to tachyphylaxis.

Doses must be constantly titrated to adjust Doses must be constantly titrated to adjust for this phenomenon and for changes in the for this phenomenon and for changes in the patients clinical condition.patients clinical condition.

Subcutaneous Drug DeliverySubcutaneous Drug Delivery

Bioavailability of subcutaneous heparin or Bioavailability of subcutaneous heparin or insulin can be reduced during treatment insulin can be reduced during treatment with vasopressors due to cutaneous with vasopressors due to cutaneous vasoconstriction.vasoconstriction.

Phenylephrine (Neosynephrine)Phenylephrine (Neosynephrine)

Purely alpha-adrenergic agonist activityPurely alpha-adrenergic agonist activity– Vasoconstriction with minimal cardiac inotropy or Vasoconstriction with minimal cardiac inotropy or

chronotropy.chronotropy. Useful in settings of hypotension with SVR < 700 Useful in settings of hypotension with SVR < 700

dynes x sec/cm5dynes x sec/cm5– Hyperdynamic sepsis, neurologic disorders, neuroaxial Hyperdynamic sepsis, neurologic disorders, neuroaxial

anesthesia induced hypotension.anesthesia induced hypotension. Contraindicated if SVR > 1200 dynes x sec/cm5Contraindicated if SVR > 1200 dynes x sec/cm5 reflex bradycardiareflex bradycardia

Norepinephrine (Levophed)Norepinephrine (Levophed) Acts on both alpha-1 and beta-1 receptorsActs on both alpha-1 and beta-1 receptors

– Potent vasoconstriction as well as a less Potent vasoconstriction as well as a less pronounced increase in cardiac outputpronounced increase in cardiac output

Reflex bradycardia usually occurs in Reflex bradycardia usually occurs in response to the increased MAPresponse to the increased MAP– Mild chronotropic effect is cancelled out and Mild chronotropic effect is cancelled out and

the HR remains unchanged or decreases the HR remains unchanged or decreases slightly.slightly.

Drug of choice to treat septic shock. Drug of choice to treat septic shock. (5)(5)

5.) ICU Book, 2007;3105.) ICU Book, 2007;310

Epinephrine (Adrenalin)Epinephrine (Adrenalin) Potent beta-1 receptor activity and beta-2 and Potent beta-1 receptor activity and beta-2 and

alpha-1 receptor effects.alpha-1 receptor effects. Result is an increased CO, with decreased SVR Result is an increased CO, with decreased SVR

and variable effects on the MAP.and variable effects on the MAP. Beta-1 receptor stimulation may provoke Beta-1 receptor stimulation may provoke

dysrhythmias.dysrhythmias. Greater degree of splanchnic vasoconstriction.Greater degree of splanchnic vasoconstriction. Most often used in ACLS, treatment of Most often used in ACLS, treatment of

anaphylaxis, as a second line agent in septic shock anaphylaxis, as a second line agent in septic shock and for management of hypotension following and for management of hypotension following OHS/CABG.OHS/CABG.

Dopamine (Intropin)Dopamine (Intropin) At low doses, dopamine acts predominately on At low doses, dopamine acts predominately on

dopamine-1 receptors in the renal mesenteric, dopamine-1 receptors in the renal mesenteric, cerebral, and coronary beds, resulting in selective cerebral, and coronary beds, resulting in selective vasodilation.vasodilation.

At moderate doses, dopamine also stimulates Beta-At moderate doses, dopamine also stimulates Beta-1 receptors and increases CO, predominately by 1 receptors and increases CO, predominately by increasing SV with variable effects on HR.increasing SV with variable effects on HR.– Can result in dose-limiting dysrhythmiasCan result in dose-limiting dysrhythmias

At higher doses, dopamine stimulates alpha At higher doses, dopamine stimulates alpha receptors and produces vasoconstriction with an receptors and produces vasoconstriction with an increased SVR.increased SVR.

Dopamine (Intropin)Dopamine (Intropin)

The dose-dependent effects of dopamine The dose-dependent effects of dopamine mean that increasing the dose of the drug is mean that increasing the dose of the drug is akin to switching vasopressors.akin to switching vasopressors.

Most often used in hypotension due to Most often used in hypotension due to sepsis or cardiac failuresepsis or cardiac failure

““Renal-dose” DopamineRenal-dose” Dopamine

Dopamine selectively increases renal blood Dopamine selectively increases renal blood flow when administered at 1-3 mcg/kg/minflow when administered at 1-3 mcg/kg/min

Currently, there is no data to support the Currently, there is no data to support the routine use of low dose dopamine to routine use of low dose dopamine to prevent or treat acute renal failure or prevent or treat acute renal failure or mesenteric ischemia.mesenteric ischemia.

Dobutamine (Dobutrex)Dobutamine (Dobutrex) Not a vasopressor but rather an inotrope that Not a vasopressor but rather an inotrope that

causes vasodilation.causes vasodilation. Predominant beta-1 receptor effect increases Predominant beta-1 receptor effect increases

inotropy and chronotropy and reduces LV filling inotropy and chronotropy and reduces LV filling pressures.pressures.

Minimal alpha and beta-2 receptor effects result in Minimal alpha and beta-2 receptor effects result in overall vasodilation, complemented by reflex overall vasodilation, complemented by reflex vasodilation to the increased CO.vasodilation to the increased CO.

Net effect is increased CO, with decreased SVR Net effect is increased CO, with decreased SVR with or without a small reduction in BP.with or without a small reduction in BP.

Dobutamine (Dobutrex)Dobutamine (Dobutrex)

Frequently used in severe, medically Frequently used in severe, medically refractory heart failure and cardiogenic refractory heart failure and cardiogenic shock.shock.

Should not be routinely used in sepsis Should not be routinely used in sepsis because of the risk of hypotension.because of the risk of hypotension.

Does not selectively vasodilate the renal Does not selectively vasodilate the renal vascular bed.vascular bed.

Phosphodiesterase InhibitorsPhosphodiesterase Inhibitors Amrinone and MilrinoneAmrinone and Milrinone Nonadrenergic drugs with inotropic and Nonadrenergic drugs with inotropic and

vasodilatory actions. Acts by inhibiting the vasodilatory actions. Acts by inhibiting the breakdown of both cAMP and cGMP by the breakdown of both cAMP and cGMP by the phosphodiesterase (PDE3) enzyme.phosphodiesterase (PDE3) enzyme.

Effects are similar to dobutamine but with a lower Effects are similar to dobutamine but with a lower incidence of dysrhythmias.incidence of dysrhythmias.

Used to treat patients with impaired cardiac Used to treat patients with impaired cardiac function and medically refractory HF.function and medically refractory HF.

Vasodilatory properties limit their use in Vasodilatory properties limit their use in hypotensive patients.hypotensive patients.

VasopressinVasopressin

Acts like ADH; directly stimulates smooth Acts like ADH; directly stimulates smooth muscle V1 receptors, resulting in muscle V1 receptors, resulting in vasoconstrictionvasoconstriction

Often used in the setting of DI or esophageal variceal Often used in the setting of DI or esophageal variceal bleeding.bleeding.

May be useful in the treatment of refractory septic May be useful in the treatment of refractory septic shock, particularly as a second pressor agent.shock, particularly as a second pressor agent.

VasopressinVasopressin Addition of vasopressin to norepinephrine was more Addition of vasopressin to norepinephrine was more

effective in reversing late vasodilatory shock than effective in reversing late vasodilatory shock than norepinephrine alone. norepinephrine alone. (1)(1)

Vasopressin did not reduce mortality compared to norepi. Vasopressin did not reduce mortality compared to norepi. (2)(2)

Timely treatment, rather then specific agent is the decisive Timely treatment, rather then specific agent is the decisive factor. factor. (3)(3)

1. Arginine Vasopressin in Advanced Vasodilatory Shock, Circulation. 2003; 107: 2313–2319.

2. Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock, NEJM. 2008; 358:877-887.

3. Septic Shock – Vasopressin, Norepinephrine, and Urgency, NEJM. 2008; 358;954-956.

VasopressinVasopressin Addition of corticosteroid to low dose vasopressin was Addition of corticosteroid to low dose vasopressin was

associated with decreased mortality and organ dysfunction associated with decreased mortality and organ dysfunction as compared to norepi and corticosteroidas compared to norepi and corticosteroid. . (4)(4)

4. Interaction of vasopressin infusion, corticosteroid treatment, and mortality of septic shock, Crit Care Med. 2009; 37; 811-818.

ComplicationsComplicationsHypoperfusionHypoperfusion

Commonly occurs in the setting of Commonly occurs in the setting of inadequate cardiac output or inadequate inadequate cardiac output or inadequate volume resuscitation.volume resuscitation.

Dusky skin changes at the tips of the fingers Dusky skin changes at the tips of the fingers and toes, renal insufficiency and oliguria, and toes, renal insufficiency and oliguria, and possible limb ischemia.and possible limb ischemia.

Increase the risk of gastritis, shock liver, Increase the risk of gastritis, shock liver, intestinal ischemia, or translocation of gut intestinal ischemia, or translocation of gut flora with resultant bacteremia.flora with resultant bacteremia.

ComplicationsComplicationsDysrhythmiasDysrhythmias

Stimulation of beta-1 receptors.Stimulation of beta-1 receptors. Increases the risk of sinus tachycardia, atrial Increases the risk of sinus tachycardia, atrial

fibrillation, AVnRT, or ventricular fibrillation, AVnRT, or ventricular tachyarrhythmias.tachyarrhythmias.

Limit the maximal dose and necessitate Limit the maximal dose and necessitate switching to another agent with less switching to another agent with less prominent beta-1 effects.prominent beta-1 effects.

ComplicationsComplicationsMyocardial ischemiaMyocardial ischemia

Beta receptor stimulation can increase Beta receptor stimulation can increase myocardial oxygen consumption.myocardial oxygen consumption.

Excessive tachycardia should be avoided Excessive tachycardia should be avoided because of impaired diastolic filling of the because of impaired diastolic filling of the coronary arteries.coronary arteries.

ComplicationsComplicationsLocal effectsLocal effects

Peripheral extravasation of vasopressors Peripheral extravasation of vasopressors into the surrounding connective tissue can into the surrounding connective tissue can lead to excessive local vasoconstriction lead to excessive local vasoconstriction with subsequent skin necrosis.with subsequent skin necrosis.

Vasopressors should be administered via a Vasopressors should be administered via a central line.central line.

Local treatment with phentolamine (5 – Local treatment with phentolamine (5 – 10mg) sub-Q can minimize local 10mg) sub-Q can minimize local vasoconstriction.vasoconstriction.

ComplicationsComplicationsHyperglycemiaHyperglycemia

May occur due to inhibition of insulin May occur due to inhibition of insulin secretion.secretion.

Magnitude of hyperglycemia generally is Magnitude of hyperglycemia generally is mild.mild.

More pronounced with norepinephrine and More pronounced with norepinephrine and epinephrine than dopamine.epinephrine than dopamine.

Vasopressor Use in Septic ShockVasopressor Use in Septic Shock Patients with hyperdynamic septic shock Patients with hyperdynamic septic shock

(hypotension, low SVR, and high CI) tend to have (hypotension, low SVR, and high CI) tend to have warm extremities due to inappropriate warm extremities due to inappropriate hyperperfusion of the skin and soft tissues.hyperperfusion of the skin and soft tissues.– Norepinephrine and phenylephrine appear more potent Norepinephrine and phenylephrine appear more potent

in hyperdynamic sepsis.in hyperdynamic sepsis. Patients with hypodynamic septic shock Patients with hypodynamic septic shock

(hypotension, low SVR, and low CI) manifest (hypotension, low SVR, and low CI) manifest hypoperfusion of the extremities.hypoperfusion of the extremities.– Dopamine may be preferable in patients with Dopamine may be preferable in patients with

hypodynamic sepsis.hypodynamic sepsis.

SACiUCI StudySACiUCI Study

Norepi associated with worse outcomes Norepi associated with worse outcomes (3.5x increase in 28d mortality risk, p= (3.5x increase in 28d mortality risk, p= <0.001).<0.001).

Dopamine may have a beneficial effect Dopamine may have a beneficial effect (0.7x lower 28d mortality, p=0.049).(0.7x lower 28d mortality, p=0.049).

6.) Influence of vasopressor agent in septic shock mortality. Results from the Portuguese 6.) Influence of vasopressor agent in septic shock mortality. Results from the Portuguese Community-Acquired Sepsis Study (SACiUCI). Crit Care Med. 2009; 37;410-416.Community-Acquired Sepsis Study (SACiUCI). Crit Care Med. 2009; 37;410-416.