Vasopressors

Vasopressors
Judith Hellman, M.D.
Judith Hellman, M.D.
Associate Professor
Associate Professor
Anesthesia and Perioperative Care
Anesthesia and Perioperative Care
University of California, San Francisco
University of California, San Francisco
Overview
Overview

Define shock states
Define shock states

Review drugs commonly used to treat hypotension
Review drugs commonly used to treat hypotension

Overview of drug management of shock states
Overview of drug management of shock states

Describe recent studies on pharmacologic management
Describe recent studies on pharmacologic management
of hypotension in septic shock
of hypotension in septic shock
VASST VASST - - Vasopressin versus Vasopressin versus Norepinephrine Norepinephrine for septic for septic
shock shock
European study European study - - Epinephrine Epinephrine vs Norepinephrine vs Norepinephrine + +
dobutamine dobutamine
Portuguese Study Portuguese Study - - Dopamine versus Dopamine versus Norepinephrine Norepinephrine
Shock States
Shock States

Cardiogenic
Cardiogenic

Hypovolemic
Hypovolemic

Obstructive
Obstructive
-
-
Impairment of normal
Impairment of normal
flow of blood
flow of blood
Obstruction of outflow Obstruction of outflow - - PE, pulmonary HTN, severe AS PE, pulmonary HTN, severe AS
Obstruction of inflow Obstruction of inflow - - Cardiac Cardiac tamponade tamponade, , pneumothorax pneumothorax

Medication effects
Medication effects
Neuraxial Neuraxial local anesthetics local anesthetics
Systemically active drugs Systemically active drugs

Distributive
Distributive

-
-
Low vascular tone, increased vascular
Low vascular tone, increased vascular
capacitance
capacitance
Sepsis and other systemic inflammatory processes Sepsis and other systemic inflammatory processes
Acute adrenal insufficiency Acute adrenal insufficiency
Neurogenic Neurogenic shock shock
Drugs Commonly Used to Treat
Drugs Commonly Used to Treat
Shock in ICUs
Shock in ICUs

Adrenergic Agents
Adrenergic Agents

Phenylephrine
Phenylephrine

Norepinephrine
Norepinephrine

Epinephrine
Epinephrine

Dopamine
Dopamine

Dobutamine
Dobutamine

Isoproterenol
Isoproterenol

Vasopressin
Vasopressin

1 2
+++

+++ ++ +
+++ +++ ++
++ ++ +
+ +++ +

+++ +++
Phenylephrine
Phenylephrine

Receptors:
Receptors:

Vascular effects:
Vascular effects:
Potent vasoconstrictor
Potent vasoconstrictor

Cardiac effects
Cardiac effects
-
-
Reflex
Reflex
Bradycardia Bradycardia
Decreased cardiac output Decreased cardiac output

Uses
Uses
Epidural and spinal anesthesia/analgesia Epidural and spinal anesthesia/analgesia
Vasodilation Vasodilation (autonomic instability, (autonomic instability, vasodilators) vasodilators)
To temporize while awaiting access for To temporize while awaiting access for other agents other agents
When agents with When agents with - -adrenergic activity cause tachycardia adrenergic activity cause tachycardia
Norepinephrine
Norepinephrine

Receptors:
Receptors:

and
and
1,
1,
minimal
minimal
2
2
-
-
>
>

Vascular effects:
Vascular effects:
Potent vasoconstrictor
Potent vasoconstrictor

Cardiac effects
Cardiac effects

Increased contractility
Increased contractility

Increased heart rate/tachycardia (variable)
Increased heart rate/tachycardia (variable)

Uses
Uses

Combined
Combined
vasodilation
vasodilation
and myocardial dysfunction
and myocardial dysfunction

Sepsis/SIRS
Sepsis/SIRS
Epinephrine
Epinephrine

Receptors:
Receptors:

and
and

-
-
=
=

Vascular effects:
Vascular effects:
Potent vasoconstrictor
Potent vasoconstrictor

Cardiac effects
Cardiac effects
More potent effect on contractility than More potent effect on contractility than norepinephrine norepinephrine
Increased heart rate/tachycardia Increased heart rate/tachycardia

Uses
Uses
When severe myocardial dysfunction is contributing to shock When severe myocardial dysfunction is contributing to shock
Cardiac arrest Cardiac arrest - - Can be given Can be given intra intra- -tracheally tracheally
Anaphylaxis Anaphylaxis

Potential Problems
Potential Problems
Reduced Reduced splanchnic splanchnic blood flow blood flow
Increased myocardial work load Increased myocardial work load ischemia, heart failure ischemia, heart failure
Dopamine
Dopamine

Receptors:
Receptors:

,
,
1>2,
1>2,
dopaminergic
dopaminergic

Vascular effects:
Vascular effects:
Vasoconstricts
Vasoconstricts
at higher doses
at higher doses

Cardiac effects
Cardiac effects
-
-
Lower doses
Lower doses
Increased cardiac output Increased cardiac output
Increased heart rate Increased heart rate

Uses
Uses
Shock from sepsis or other systemic inflammatory processes Shock from sepsis or other systemic inflammatory processes
To increase urine output (low dose, To increase urine output (low dose, dopaminergic dopaminergic effect) effect)

Potential problems
Potential problems
Dysrhythmias Dysrhythmias - - Atrial Atrial fibrillation, fibrillation, ST ST
Not a potent vasoconstrictor Not a potent vasoconstrictor - - often often need need additional additional pressors pressors
Dobutamine
Dobutamine

Receptors:
Receptors:

1>
1>

2
2

Cardiac
Cardiac
effects:
effects:

1
1
Increased cardiac output Increased cardiac output - - Strong Strong inotrope inotrope
Increased heart rate Increased heart rate

Vascular effects:
Vascular effects:

2,
2,
Vasodilation
Vasodilation

Effect on BP variable
Effect on BP variable

Uses
Uses
Cardiogenic Cardiogenic shock shock
Refractory shock from sepsis or other systemic inflammatory Refractory shock from sepsis or other systemic inflammatory
process process

Potential problems
Potential problems
Tachydysrhythmias Tachydysrhythmias
Hypotension can occur 2 Hypotension can occur 2 to to 2 effects 2 effects
Vasopressin
Vasopressin

Hormone with many effects: vascular, renal, endocrine
Hormone with many effects: vascular, renal, endocrine

Vascular
Vascular
Important role in BP regulation Important role in BP regulation
Variable vasoconstriction and Variable vasoconstriction and vasodilation vasodilation of vascular beds of vascular beds

Vasopressin levels are decreased in sepsis
Vasopressin levels are decreased in sepsis

Uses
Uses
Shock from sepsis and other inflammatory processes Shock from sepsis and other inflammatory processes - - Low dose Low dose
Peri Peri- -cardiopulmonary cardiopulmonary bypass bypass
Instead of Instead of epinephrine during epinephrine during cardiorespiratory cardiorespiratory arrest arrest
Hypotension due to ACE inhibitor Hypotension due to ACE inhibitor

Potential problems
Potential problems
Reduced GI blood flow, even at Reduced GI blood flow, even at low dose low dose
Cardiac ischemia Cardiac ischemia
Vasoactive
Vasoactive
Drug Management
Drug Management
of Shock States
of Shock States
Cardiogenic
Cardiogenic
Shock
Shock

Dobutamine
Dobutamine

Norephinephrine
Norephinephrine

Epinephrine
Epinephrine

Phosphdiesterase
Phosphdiesterase
inhibitors
inhibitors
-
-
Amrinone/milrinone
Amrinone/milrinone
Hypovolemic
Hypovolemic
Shock
Shock
Fluid resuscitation!!
Fluid resuscitation!!
Obstructive Forms of Shock
Obstructive Forms of Shock

Outflow problems
Outflow problems
-
-
PE,
PE,
Aortic
Aortic
coarctation
coarctation
, Aortic
, Aortic
stenosis
stenosis
, pulmonary HTN
, pulmonary HTN
Judicious fluids Judicious fluids
Inotropes Inotropes or mixed or mixed inotrope/vasoconstrictor inotrope/vasoconstrictor - - dobutamine dobutamine, ,
norepinephrine norepinephrine

Inflow problems
Inflow problems
-
-
Cardiac
Cardiac
tamponade
tamponade
,
,
pneumothorax
pneumothorax
Fluids Fluids
Relieve source Relieve source ( (pericardiocentesis pericardiocentesis, chest tube) , chest tube)
Medication
Medication
-
-
Induced Shock
Induced Shock

Pathophysiology
Pathophysiology
Vasodilation Vasodilation
Cardiac dysfunction Cardiac dysfunction

Neuraxial
Neuraxial
blockade
blockade
-
-
Phenylephrine
Phenylephrine

Systemic vasodilators
Systemic vasodilators
-
-
Phenylephrine
Phenylephrine
or
or
norepinephrine
norepinephrine
(depending on additional factors)
(depending on additional factors)

Cardiac depressants
Cardiac depressants
Inotrope Inotrope such as such as dobutamine dobutamine
Consider Consider norepinephrine norepinephrine if suspect concomitant if suspect concomitant vasodilation vasodilation
Shock Associated with Systemic
Shock Associated with Systemic
Inflammatory Process
Inflammatory Process
Shock Associated with Inflammation
Shock Associated with Inflammation

Agents used routinely to treat hypotension due to sepsis
Agents used routinely to treat hypotension due to sepsis
and other systemic inflammatory processes:
and other systemic inflammatory processes:
Norephinephrine Norephinephrine
Dopamine Dopamine
Vasopressin Vasopressin
Phenylephrine Phenylephrine
Dobutamine Dobutamine
Epinephrine Epinephrine

Physiology of
Physiology of
hypotension in systemic inflammatory
hypotension in systemic inflammatory
processes
processes
Decreased vascular tone Decreased vascular tone increased vascular capacitance increased vascular capacitance
Decreased myocardial contractility Decreased myocardial contractility
VASST Trial:
VASST Trial:
Vasopressin versus
Vasopressin versus
Norepinephrine
Norepinephrine

Hypothesis: Low dose vasopressin
Hypothesis: Low dose vasopressin

decrease mortality
decrease mortality
vs norepinephrine
vs norepinephrine
(NE) in septic shock
(NE) in septic shock

Inclusion criteria
Inclusion criteria
SIRS SIRS w/documented w/documented or suspected infection or suspected infection
NE at NE at 5 5 g/min g/min
New organ dysfunction New organ dysfunction

Interventions
Interventions

Vasopressin 0.01
Vasopressin 0.01
-
-
0.03U/min
0.03U/min
vs
vs
NE at 5
NE at 5
-
-
15
15 g/min g/min

Titrate other
Titrate other
pressor
pressor
(s) to
(s) to
achieve BP goals
achieve BP goals

Primary Endpoint: 28 day mortality
Primary Endpoint: 28 day mortality
NEJM 2008; 28;358(9):877 NEJM 2008; 28;358(9):877- -87 87
VASST: Results
VASST: Results

Subjects
Subjects
-
-
778 patients randomized
778 patients randomized
Vasopressin Vasopressin 396 396
NE 382 NE 382

Outcome
Outcome
Overall no reduction in 28d (Primary endpoint, P0.26) or 90d Overall no reduction in 28d (Primary endpoint, P0.26) or 90d
mortality (P 0.11) mortality (P 0.11)
No No significant differences in serious adverse events significant differences in serious adverse events
Subgroups Subgroups
More severe More severe NE > 15mcg/min NE > 15mcg/min Higher mortality in Higher mortality in
vasopressin group vasopressin group
Less severe Less severe NE 5 NE 5- -15 mcg/min 15 mcg/min - - Lower mortality at 28d Lower mortality at 28d
(P 0.05) (P 0.05)
Recommendations about Vasopressin
Recommendations about Vasopressin
Based on Available Data
Based on Available Data

Consider using vasopressin in:
Consider using vasopressin in:
Patients with septic shock that are on a mid Patients with septic shock that are on a mid- -range dose of range dose of
NE (5 NE (5- -15 mcg/min) 15 mcg/min)
Patients that develop Patients that develop tachydysrhythmias tachydysrhythmias on NE on NE
Patients that are extremely Patients that are extremely acidemic acidemic so won so won t respond as well t respond as well
to NE (vasopressin not inactivated by low pH) to NE (vasopressin not inactivated by low pH)
Patients on extremely high doses of NE Patients on extremely high doses of NE
ACLS ACLS as an alternative to epinephrine as an alternative to epinephrine
Peri Peri- -CPB CPB
European Trial: Epinephrine versus
European Trial: Epinephrine versus
Norepinephrine
Norepinephrine
+
+
Dobutamine
Dobutamine

Hypothesis:
Hypothesis: Epi Epi may be better than NE + may be better than NE + Dobutamine Dobutamine based based
on more on more activity activity

Study Design:
Study Design: Randomized Randomized trial of patients with septic shock trial of patients with septic shock

Subjects:
Subjects: 330 patients randomized 330 patients randomized
Epinephrine 161 Epinephrine 161
NE + NE + Dobutamine Dobutamine 169 169

Outcome
Outcome
Overall no reduction in 28d mortality (Primary endpoint, P Overall no reduction in 28d mortality (Primary endpoint, P
0.31) or other secondary endpoints 0.31) or other secondary endpoints
No No significant differences in serious adverse events significant differences in serious adverse events

Conclusions
Conclusions
No significant difference No significant difference
Lancet. 2007 Aug 25;370(9588):676-84
Dopamine:
Dopamine: Sepsis Occurrence in
Acutely Ill Patients (SOAP) Study

Hypothesis:
Hypothesis: DA worsens outcome in shock

Study Design: Observational study in 198 ICUs
Study Design: Observational study in 198 ICUs

Subjects: 1058 patients with shock; 462 patients with
Subjects: 1058 patients with shock; 462 patients with
septic shock
septic shock
NE: 80.2%; 31.8% received only NE NE: 80.2%; 31.8% received only NE
DA: 35.4%; 8.8% %; 8.8% received only DA received only DA
Epi: 23.3%; 4.5% only Epi: 23.3%; 4.5% only epi epi
Dobutamine Dobutamine + + catecholamines catecholamines 33.9% 33.9%

Outcome
Outcome
DA and epinephrine used more in non DA and epinephrine used more in non- -survivors survivors
DA DA an independent risk factor for mortality in patients with an independent risk factor for mortality in patients with
shock, and in the subcategory of patients with septic shock shock, and in the subcategory of patients with septic shock
Crit Care Med. 2006;34(3):589-97
Portuguese
Portuguese Community Acquired
Sepsis Study
:
:
Dopamine (DA)
Dopamine (DA)
vs
vs
NE
NE

Hypothesis:
Hypothesis:

Study Design:
Study Design: Multicenter Multicenter, observational study of patients with , observational study of patients with
community community- -acquired sepsis in 17 ICUs acquired sepsis in 17 ICUs

Subjects:
Subjects: 458 patients with septic shock 458 patients with septic shock
73% received NE 73% received NE
50.5% received DA 50.5% received DA

Outcome
Outcome
NE associated with worse outcome NE associated with worse outcome
NE independent risk factor for ICU mortality in septic shock NE independent risk factor for ICU mortality in septic shock
Crit Care Med. 2009;37(2):410-6
Surviving Sepsis Campaign:
Surviving Sepsis Campaign:
2008 Guidelines
2008 Guidelines
Vasopressors
NE and DA are the initial vasopressors of choice
Epinephrine, phenylephrine, or vasopressin should not be
administered as the initial vasopressor in septic shock
Vasopressin 0.03 units/min may be subsequently added to
NE
Use epinephrine as the first alternative agent in septic shock
when blood pressure is poorly responsive to NE or DA.
Do not use low-dose dopamine for renal protection
Inotropic therapy
Use dobutamine in patients with myocardial dysfunction
Crit Care Med. 2008 J an;36(1):296-327
Thank You!!
Gram-negative
Bacteria
Terlipressin
Terlipressin

Vasopressin analogue
Vasopressin analogue
Longer acting than vasopressin (half Longer acting than vasopressin (half- -life ~ 6 hours versus 6 life ~ 6 hours versus 6
minutes) minutes)

Widely used in
Widely used in
Europe
Europe
Undergoing Undergoing trials in US trials in US

Uses
Uses
Shock associated with sepsis and other systemic inflammatory Shock associated with sepsis and other systemic inflammatory
processes processes

Potential problems
Potential problems
Decreased cardiac output Decreased cardiac output