Transcript Epinephrine
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®)
DOPAMINENOREPIEPINEPHRINE
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