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Vasopressors,
Inotropes, and Shock
Beatrice Wong, PharmD, BCPS
November 1, 2011
Objectives

Define types of shock.

Review pharmacology of vasoactive agents.

Overview of management of the different types
of shock.

Discuss cases.
Shock

Physiologic state of impaired tissue perfusion
and oxygen delivery

Cardinal signs
• Hypotension (SBP <90 mmHg or >40 mmHg decrease
from baseline)
• Oliguria
• Altered mental status
• Metabolic acidosis
• Cool, clammy skin
Classification
Cardiogenic
Distributive
Hypovolemic
• Nonmechanical: Myocardial infarction, low cardiac
output syndrome, end-stage cardiomyopathy
• Mechanical: Rupture of septum or free wall, mitral or
aortic insufficiency, papillary muscle rupture,
pericardial tamponade
•
•
•
•
Sepsis
Anaphylaxis
Neurogenic
Drug- induced
• Hemorrhagic: GI bleed, trauma, internal bleeding
• Nonhemorrhagic: Dehydration, sequestration,
cutaneous loss
Applied therapeutics: the clinical use of drugs, 7th ed.
The Internet Journal of Anesthesiology. 2007 Volume 11 Number 2
Hemodynamic Indices
Parameter
Normal Value
Cardiac Output (CO)
4-7 L/min
Cardiac Index (CI)
2.5-4.2 L/min/m2
Central Venous Pressure (CVP)
2-7 mm Hg
Mixed Venous Oxygen Saturation (SvO2)
70-80%
Mean Arterial Pressure (MAP)
80-100 mm Hg
Pulmonary Artery Pressure
20-30/8-12 mm Hg
Pulmonary Capillary Wedge Pressure (PCWP)
5-12 mm Hg
Systemic Vascular Resistance (SVR)
800-1,440 dyne ∙s ∙cm5
Swan Ganz Interpretation
Physiologic
State
CO
PCWP
SVR
Cardiogenic
↓
↑
↑
Distributive
↑
↓ or ↔
↓
Hypovolemic
↓
↓
↑
CO= Cardiac output, PCWP= Pulmonary capillary wedge pressure, SVR= Systemic vascular resistance
Goals of Care

Restore effective tissue perfusion, normalize
cellular metabolism
• Hemodynamic therapy
• Fluid resuscitation
• Vasopressor therapy
• Acidosis may decrease effects of catecholamines
• Utilization of sodium bicarbonate?
• Inotropic therapy
Regulating Blood Pressure
Receptor
Organ Distribution
Effect
α1
Vascular smooth muscle
Vasoconstriction
β1
Heart
↑ Contractility, ↑ Heart rate
β2
Respiratory, vascular
smooth muscle
Vasodilation
D1
Vascular smooth muscle
Vasodilation
V1
Vascular smooth muscle
Vasoconstriction
V2
Kidneys
↑ Reabsorption of water
(kidneys, CNS, coronary)
Catecholamines
β
Isoproterenol
Dopexamine
Dobutamine
Dopamine
Epinephrine
Norepinephrine
Phenylephrine
α
Vasoactive Agents
Receptor Specificity
Pharmacologic Effect
Drug
Dose Range
α1
β1
β2
Vasodilation
Vasoconstriction
Contractility
Heart
Rate
Dobutamine
2.5-15 g/kg/min
+
+++
++
++
-
+++
+
Dopamine
0.5-2 g/kg/min
-
-
-
-
-
-
-
2-5 g/kg/min
-
+
-
-
+
+
+
5-10 g/kg/min
+
++
-
-
++
++
++
15-20 g/kg/min
+++
++
-
-
+++
++
++
0.01-0.1
g/kg/min
+
+++
++
+
+
+++
++
>0.1 g/kg/min
+++
++
++
-
+++
++
++
Isoproterenol
0.01-0.1
g/kg/min
-
++++
+++
+++
-
+++
+++
Milrinone
0.375-0.75
g/kg/min
-
-
-
++
-
++
-
Norepinephrine
0.05-1 g/kg/min
++++
++
-
-
++++
+
+
Phenylephrine
0.5-5 g/kg/min
+++
-
-
-
+++
-
-
Vasopressin
0.01-0.1 units/hr
-
-
-
-
+++
-
-
Epinephrine
Applied Therapeutics: the clinical use of drugs, 7th edition.
Treatment
Physiologic State
Treatment
Distributive
Fluids
Vasopressors
Antibiotics
Cardiogenic
Inotropes
Afterload reducers
Diuretics
Hypovolemic
Fluids
Colloids
Blood products
Vasoactive Agents
Vasopressors
 Inotropes
 Vasodilators

Vasopressor Agents

Catecholamines
•
•
•
•
Dopamine
Epinephrine
Norepinephrine (Levophed®)
Phenylephrine (Neosynephrine®)
DOPAMINENOREPIEPINEPHRINE

Miscellaneous agents
• Vasopressin
Vasoactive Therapy

Adverse Effects
• Arrhythmias
• Direct effect of beta-1 stimulation
• ↑ oxygen demand by the heart
• Regional Hypoperfusion
• Possible organ hypoperfusion at the expense of
restoring central BP (e.g. kidney, gastrointestinal)
• Endocrine Effects
• Hyperglycemia
• Tissue Damage and Extravastation
• Tachyphylaxis may occur with prolonged use
Dopamine


Most common first line catecholamine
MOA: dose-related receptor activity

Dosing

Considerations
• DA, beta-1, alpha-1
• ↑ BP via ↑ myocardial contractility and
vasoconstriction
• 0.5 – 20 mcg/kg/min
DA: 0.5-3 mcg/kg/min
Beta-1: 3-10 mcg/kg/min
Alpha-1: > 10 mcg/kg/min
• Dose response is highly variable
• “Renal” dosing: Low-dose dopamine should not
be used to prevent renal failure
• Tachydysrhythmias are common
Epinephrine
More often used for inotropic effects in patients
with ↓ CO/CI and ↓SVR
 MOA: dose-dependent hemodynamic effect
 Dosing – split dosing effect

• 0.01-0.1 mcg/kg/min (β1, β2 effects predominate)
• > 0.1-1 mcg/kg/min (α1 effects predominate)

Considerations
• Metabolic derangements
Norepinephrine

Vasoconstriction predominates over CO or
HR effect
• Improved regional perfusion than higher dose
dopamine


MOA: alpha >>> beta effects
Dosing
• 0.01 – 1 mcg/kg/min

Considerations
• Splanchnic perfusion
Phenylephrine

Selective alpha agonist producing ↑SVR
• May decrease HR, CO and cause coronary
constriction


MOA: alpha-1 mediated vasoconstriction
Dosing
• 0.5 – 5 mcg/kg/min

Considerations
• Useful in pts with significant tachycardia
Vasopressin

Renal Actions
• Antidiuretic hormone (ADH), concentrates urine by
increasing the flow of water from the collecting ducts
into the renal medulla

Vascular Actions
• Direct action on vascular smooth muscle (V1 receptor)
• Increases vascular resistance in the mesenteric beds,
reducing portal venous flow
• Increases vascular reactivity to catecholamines
• Coronary artery vasoconstriction has been reported
especially at high doses (>0.1u/min may need
nitroglycerin gtt)
Vasopressin

Dosing
• 0.01-0.1 u/min
• 0.04 units/min in sepsis (not titrated)
 Onset: immediate
 t1/2: 10-20mins
 Titration
• 0.01-0.02 units/min q 30 minutes

Monitoring
• Decreased cardiac output
• Peripheral vasoconstriction and ischemia
Vasopressin

Advantages
•
•
•
•

Long half-life
Works independently of adrenergic receptors
Works in acidotic patients
Doesn’t appear to elevate PA pressures
Disadvantages
• Decreased mesenteric perfusion
Inotropes





Dopamine
Dobutamine
Epinephrine
Isoproterenol (Isuprel®)
Milrinone (Primacor®)
Dobutamine


Cardiogenic shock, heart failure
MOA

Dosing

Considerations
• Selective beta-2 agonist, ↑CO and HR
• 1-20 mcg/kg/min
• Dose > 10 mcg/kg/min rarely used
• Dose-related tachyarrhythmias
• ↑ mVO2 – caution in ischemia, CAD pts
Isoproterenol
Think of this agent as a chemical
pacemaker
 MOA: beta-1 and beta-2 mediate
effects

• ↑ HR and CO; ↓ SVR

Dosing

Considerations
• 0.01 to 0.1 mcg/kg/min
• Primary use is as a HR agent in post-heart
transplant patients
• Titrating drug to HR not MAP
Milrinone


“Inodilator”
MOA
• Phosphodiesterase inhibitor - ↑cAMP levels leading to
smooth muscle relaxation and increased cardiac
contractility

Dosing
• 0.25 – 0.75 mcg/kg/min

Considerations
• Accumulates in renal dysfunction
• Clinically significant hypotension – avoid loading
• Good alternative to dobutamine in HF patients with ↑ PA
pressures
• Commonly used with vasopressin for milrinone-induced
hypotension
Vasodilators
Sodium Nitroprusside (Nipride®)
 Nitroglycerin
 Nesiritide (Natrecor®)

Nitroprusside


Direct active arterial vasodilator
Dosing
• 0.25-5 mcg/kg/min (max 10 mcg/kg/min)
• Half life 3-5 minutes, fast onset 1-10mins

Main uses
• Hypertension
• Aortic dissection (use with beta-blocker)
• CHF w/ “elevated” BP

Considerations
• Renal insufficiency – accumulation of thiocyanate
• Liver insufficiency – accumulation of cyanide
• May increase ICP
Nitroglycerin


Primary role in pts with ACS
MOA
• Relaxation of smooth muscle

Dosing
• 0.1-4 mcg/kg/min, can be titrated quickly for chest
pain

Considerations
• Tolerance occurs within 24 hrs
• Headache
• Rebound tachycardia
Nesiritide



Targeted for ADHF patients
MOA – numerous (see next slide)
Dosing
• 0.005-0.02 mcg/kg/min
• Generally avoid bolus dosing

Considerations
• Synergy with other vasodilators
• Used in combination with inotropes
Nesiritide

Hemodynamic:
• Vasodilation of arteries, veins, and coronaries
•  Preload and  Cardiac Output
•  Lusitropy

Neuroendocrine:
• Counter-regulatory effect on RAAS,  Aldosterone
•  SNS activity,  Endothelin

Renal:
•  GFR,  Diuresis and Natriuresis
Levin ER et al, NEJM 1998; Venugopal J, Journal Clinical Pharmacy and Therapeutics 2001
Case 1
A 90 yo woman is admitted with urosepsis
and septic shock. Her BP is 72/44, HR 120,
O2 saturation of 99%. BUN 74mg/dL, SCr
2.7mg/dL. Empiric antibiotics initiated.
What should be started next?
A.
B.
C.
D.
Dobutamine
Epinephrine
Normal saline
Vasopressin
Case 1 continued
Patient’s CVP ↑ to 8 mmHg. MAP ↓
to 50s. Besides continuing fluid
resuscitation, what agent would you like to
start?
A.
B.
C.
D.
Dobutamine
Milrinone
Dopamine
Epinephrine
Which agent to choose in sepsis?
CATS Study

Randomized, double-blind study in France

N= 330 patients with septic shock

Epinephrine vs Dobutamine +
Norepinephrine

Primary outcome= 28 day mortality
Lancet 2007;370:676-84.
CATS
No significant
differences in:
•Length of stay
•Pressor-free days
•Days not in
intensive care units
Overall (n=330)
Epinephrine (n=161)
Norepinephrine plus
dobutamine (n=169)
Supraventricular tachycardia
>150 bpm
41 (12%)
19 (12%)
22 (13%)
Ventricular arrhythmias
20 (6%)
12 (7%)
8 (5%)
Acute coronary event
8 (2%)
5 (3%)
3 (2%)
Limb ischaemia
8 (2%)
2 (1%)
6 (4%)
Stroke
4 (1%)
2 (1%)
2 (1%)
3 (2%)
0 (0%)
During catecholamine infusion
Central nervous system bleeding 3 (0·9%)
After catecholamine infusion
Arrhythmias
13 (4%)
6 (4%)
7 (4%)
Stroke
4 (1%)
2 (1%)
2 (1%)
Other neurological sequelae
2 (0·6%)
1 (0·6%)
1 (0·6%)
Others
6 (2%)
3 (2%)
3 (2%)
VASST Study

Randomized, double-blind trial

N=778 pts with septic shock receiving
Norepinephrine

Vasopressin 0.01-0.03 units/min vs
Norepi 5-15 mcg/min in addition to open
label vasopressors

Primary outcome=28 day mortality
NEJM 2008;358:877-87.
VASST
NEJM 2008;358:877-87.
SOAP II

Randomized, double-blind trial

N=1679 pts with shock

Dopamine vs Norepinephrine as first-line
vasopressor

Primary outcome=28 day mortality
NEJM 2010;362:779-89.
SOAP II

Cause of shock
 Sepsis 60%
 Cardiogenic source 16%
 Hypovolemia 16%
 Other 6%
NEJM 2010;362:779-89.
SOAP II
NEJM 2010;362:779-89.
SOAP II
NEJM 2010;362:779-89.
Agent of Choice in Sepsis

Surviving Sepsis Guidelines
• No high quality evidence to recommend one
catecholamine over another.
• Dopamine or Norepinephrine as 1st line
• Norepinephrine is more potent.
• Dopamine may be more useful in patients with
compromised systolic function.
• Epinephrine suggested as first alternative in septic
shock poorly responsive to 1st line tx (grade 2B)
• Vasopressin may be added to Norepinephrine.
Crit Care Med 2008;36:296-327.
Case 1 continued
Patient’s CVP ↑ to 8 mmHg. MAP ↓
to 50s. Besides continuing fluid
resuscitation, what agent would you like to
start?
A. Dobutamine
B. Milrinone
C.Norepinephrine
D.Epinephrine
Case 2

A 64 yo male has undergone surgery and is
now in the ICU. PMH: Cardiomyopathy with
EF 20%, DM II
BP 75/40, HR 110
CI= 1.8
PCWP =22
SVR= 1457
What intervention would you like to initiate?
A.
B.
C.
Normal saline
Dopamine
Sodium Nitroprusside
Questions