VasopressorsVasopressors

Judith Hellman, M.D.Judith Hellman, M.D.Associate ProfessorAssociate Professor

Anesthesia and Perioperative CareAnesthesia and Perioperative CareUniversity of California, San FranciscoUniversity of California, San Francisco

OverviewOverview Define shock statesDefine shock states Review drugs commonly used to treat hypotensionReview drugs commonly used to treat hypotension Overview of drug management of shock statesOverview of drug management of shock states Describe recent studies on pharmacologic management Describe recent studies on pharmacologic management

of hypotension in septic shockof hypotension in septic shock VASST VASST -- Vasopressin versus Vasopressin versus Norepinephrine Norepinephrine for septic for septic

shockshock European study European study -- Epinephrine Epinephrine vs Norepinephrine vs Norepinephrine + +

dobutaminedobutamine Portuguese Study Portuguese Study -- Dopamine versus Dopamine versus NorepinephrineNorepinephrine

Shock StatesShock States CardiogenicCardiogenic Hypovolemic Hypovolemic Obstructive Obstructive -- Impairment of normalImpairment of normal flow of bloodflow of blood

Obstruction of outflow Obstruction of outflow -- PE, pulmonary HTN, severe ASPE, pulmonary HTN, severe AS Obstruction of inflow Obstruction of inflow -- Cardiac Cardiac tamponadetamponade, , pneumothoraxpneumothorax

Medication effectsMedication effects Neuraxial Neuraxial local anestheticslocal anesthetics Systemically active drugsSystemically active drugs

DistributiveDistributive -- Low vascular tone, increased vascular Low vascular tone, increased vascular capacitancecapacitance Sepsis and other systemic inflammatory processesSepsis and other systemic inflammatory processes Acute adrenal insufficiencyAcute adrenal insufficiency Neurogenic Neurogenic shockshock

Drugs Commonly Used to TreatDrugs Commonly Used to TreatShock in ICUsShock in ICUs

Adrenergic AgentsAdrenergic Agents

PhenylephrinePhenylephrine NorepinephrineNorepinephrine EpinephrineEpinephrine DopamineDopamine DobutamineDobutamine IsoproterenolIsoproterenol

VasopressinVasopressin

1 2+++ +++ ++ +

+++ +++ ++

++ ++ +

+ +++ +

+++ +++

PhenylephrinePhenylephrine Receptors: Receptors: Vascular effects: Vascular effects: Potent vasoconstrictorPotent vasoconstrictor Cardiac effectsCardiac effects -- ReflexReflex

BradycardiaBradycardia Decreased cardiac outputDecreased cardiac output

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

NorepinephrineNorepinephrine Receptors: Receptors: and and 1, 1, minimal minimal 2 2 -- > > Vascular effects: Vascular effects: Potent vasoconstrictorPotent vasoconstrictor Cardiac effectsCardiac effects Increased contractilityIncreased contractility Increased heart rate/tachycardia (variable)Increased heart rate/tachycardia (variable)

UsesUses Combined Combined vasodilation vasodilation and myocardial dysfunctionand myocardial dysfunction Sepsis/SIRSSepsis/SIRS

EpinephrineEpinephrine Receptors: Receptors: and and -- = = Vascular effects: Vascular effects: Potent vasoconstrictorPotent vasoconstrictor Cardiac effectsCardiac effects

More potent effect on contractility than More potent effect on contractility than norepinephrinenorepinephrine Increased heart rate/tachycardiaIncreased heart rate/tachycardia

UsesUses When severe myocardial dysfunction is contributing to shockWhen severe myocardial dysfunction is contributing to shock Cardiac arrest Cardiac arrest -- Can be givenCan be given intraintra--tracheallytracheally AnaphylaxisAnaphylaxis

Potential ProblemsPotential Problems Reduced Reduced splanchnic splanchnic blood flowblood flow Increased myocardial work load Increased myocardial work load ischemia, heart failureischemia, heart failure

DopamineDopamine Receptors: Receptors: , , 1>2, 1>2, dopaminergicdopaminergic Vascular effects: Vascular effects: Vasoconstricts Vasoconstricts at higher dosesat higher doses Cardiac effects Cardiac effects -- Lower dosesLower doses

Increased cardiac outputIncreased cardiac output Increased heart rateIncreased heart rate

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

Potential problemsPotential problems Dysrhythmias Dysrhythmias -- Atrial Atrial fibrillation,fibrillation, STST Not a potent vasoconstrictor Not a potent vasoconstrictor -- oftenoften needneed additional additional pressorspressors

DobutamineDobutamine Receptors: Receptors: 1> 1> 22 CardiacCardiac effects: effects: 11

Increased cardiac output Increased cardiac output -- Strong Strong inotropeinotrope Increased heart rateIncreased heart rate

Vascular effects: Vascular effects: 2, 2, VasodilationVasodilation Effect on BP variableEffect on BP variable UsesUses

Cardiogenic Cardiogenic shockshock Refractory shock from sepsis or other systemic inflammatory Refractory shock from sepsis or other systemic inflammatory

processprocess Potential problemsPotential problems

TachydysrhythmiasTachydysrhythmias Hypotension can occur 2Hypotension can occur 2 toto 2 effects2 effects

VasopressinVasopressin Hormone with many effects: vascular, renal, endocrineHormone with many effects: vascular, renal, endocrine VascularVascular

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

Vasopressin levels are decreased in sepsisVasopressin levels are decreased in sepsis UsesUses

Shock from sepsis and other inflammatory processes Shock from sepsis and other inflammatory processes -- Low dose Low dose PeriPeri--cardiopulmonary cardiopulmonary bypassbypass Instead ofInstead of epinephrine during epinephrine during cardiorespiratory cardiorespiratory arrestarrest Hypotension due to ACE inhibitorHypotension due to ACE inhibitor

Potential problemsPotential problems Reduced GI blood flow, even atReduced GI blood flow, even at low doselow dose Cardiac ischemiaCardiac ischemia

Vasoactive Vasoactive Drug Management Drug Management of Shock Statesof Shock States

Cardiogenic Cardiogenic ShockShock

Dobutamine Dobutamine NorephinephrineNorephinephrine EpinephrineEpinephrine Phosphdiesterase Phosphdiesterase inhibitors inhibitors -- Amrinone/milrinoneAmrinone/milrinone

Hypovolemic Hypovolemic ShockShock

Fluid resuscitation!!Fluid resuscitation!!

Obstructive Forms of ShockObstructive Forms of Shock

Outflow problems Outflow problems -- PE,PE, Aortic Aortic coarctationcoarctation, Aortic , Aortic stenosisstenosis, pulmonary HTN, pulmonary HTN Judicious fluidsJudicious fluids Inotropes Inotropes or mixed or mixed inotrope/vasoconstrictor inotrope/vasoconstrictor -- dobutaminedobutamine, ,

norepinephrinenorepinephrine Inflow problems Inflow problems -- Cardiac Cardiac tamponadetamponade, , pneumothoraxpneumothorax

FluidsFluids Relieve sourceRelieve source ((pericardiocentesispericardiocentesis, chest tube), chest tube)

MedicationMedication--Induced ShockInduced Shock

PathophysiologyPathophysiology VasodilationVasodilation Cardiac dysfunctionCardiac dysfunction

Neuraxial Neuraxial blockade blockade -- PhenylephrinePhenylephrine Systemic vasodilators Systemic vasodilators -- Phenylephrine Phenylephrine or or

norepinephrine norepinephrine (depending on additional factors)(depending on additional factors) Cardiac depressantsCardiac depressants

Inotrope Inotrope such as such as dobutaminedobutamine Consider Consider norepinephrine norepinephrine if suspect concomitant if suspect concomitant vasodilationvasodilation

Shock Associated with Systemic Shock Associated with Systemic Inflammatory ProcessInflammatory Process

Shock Associated with InflammationShock 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: NorephinephrineNorephinephrine DopamineDopamine VasopressinVasopressin PhenylephrinePhenylephrine DobutamineDobutamine EpinephrineEpinephrine

Physiology ofPhysiology of hypotension in systemic inflammatory hypotension in systemic inflammatory processesprocesses Decreased vascular tone Decreased vascular tone increased vascular capacitanceincreased vascular capacitance Decreased myocardial contractilityDecreased myocardial contractility

VASST Trial: VASST Trial: Vasopressin versus Vasopressin versus NorepinephrineNorepinephrine

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 criteriaInclusion criteria SIRS SIRS w/documented w/documented or suspected infectionor suspected infection NE at NE at 5 5 g/ming/min New organ dysfunctionNew organ dysfunction

Interventions Interventions Vasopressin 0.01Vasopressin 0.01--0.03U/min 0.03U/min vs vs NE at 5NE at 5--15 15 g/ming/min Titrate other Titrate other pressorpressor(s) to(s) to achieve BP goalsachieve BP goals

Primary Endpoint: 28 day mortalityPrimary Endpoint: 28 day mortalityNEJM 2008; 28;358(9):877NEJM 2008; 28;358(9):877--8787

VASST: ResultsVASST: Results

Subjects Subjects -- 778 patients randomized778 patients randomized VasopressinVasopressin 396396 NE 382 NE 382

OutcomeOutcome 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) NoNo significant differences in serious adverse eventssignificant differences in serious adverse events Subgroups Subgroups

More severe More severe NE > 15mcg/min NE > 15mcg/min Higher mortality in Higher mortality in vasopressin groupvasopressin group

Less severe Less severe NE 5NE 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 DataBased on Available Data

Consider using vasopressin in: Consider using vasopressin in: Patients with septic shock that are on a midPatients with septic shock that are on a mid--range dose of range dose of

NE (5NE (5--15 mcg/min)15 mcg/min) Patients that develop Patients that develop tachydysrhythmias tachydysrhythmias on NEon NE Patients that are extremely Patients that are extremely acidemic acidemic so wonso wont 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 NEPatients on extremely high doses of NE ACLS ACLS as an alternative to epinephrineas an alternative to epinephrine PeriPeri--CPBCPB

European Trial: Epinephrine versus European Trial: Epinephrine versus Norepinephrine Norepinephrine + + DobutamineDobutamine

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

Study Design:Study Design: RandomizedRandomized trial of patients with septic shocktrial of patients with septic shock Subjects:Subjects: 330 patients randomized330 patients randomized

Epinephrine 161Epinephrine 161 NE + NE + Dobutamine Dobutamine 169 169

OutcomeOutcome Overall no reduction in 28d mortality (Primary endpoint, P Overall no reduction in 28d mortality (Primary endpoint, P

0.31) or other secondary endpoints0.31) or other secondary endpoints NoNo significant differences in serious adverse eventssignificant differences in serious adverse events

ConclusionsConclusions No significant differenceNo 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 ICUsStudy Design: Observational study in 198 ICUs Subjects: 1058 patients with shock; 462 patients with Subjects: 1058 patients with shock; 462 patients with

septic shockseptic shock NE: 80.2%; 31.8% received only NENE: 80.2%; 31.8% received only NE DA: 35.4%; 8.8%%; 8.8% received only DAreceived only DA Epi: 23.3%; 4.5% only Epi: 23.3%; 4.5% only epiepi Dobutamine Dobutamine + + catecholamines catecholamines 33.9%33.9%

OutcomeOutcome DA and epinephrine used more in nonDA and epinephrine used more in non--survivorssurvivors DADA 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 shockshock, and in the subcategory of patients with septic shockCrit Care Med. 2006;34(3):589-97

Portuguese Portuguese Community AcquiredSepsis Study :: Dopamine (DA) Dopamine (DA) vs vs NENE

Hypothesis:Hypothesis: Study Design:Study Design: MulticenterMulticenter, observational study of patients with , observational study of patients with

communitycommunity--acquired sepsis in 17 ICUsacquired sepsis in 17 ICUs Subjects:Subjects: 458 patients with septic shock458 patients with septic shock

73% received NE73% received NE 50.5% received DA50.5% received DA

OutcomeOutcome NE associated with worse outcomeNE associated with worse outcome NE independent risk factor for ICU mortality in septic shockNE independent risk factor for ICU mortality in septic shock

Crit Care Med. 2009;37(2):410-6

Surviving Sepsis Campaign:Surviving Sepsis Campaign:2008 Guidelines2008 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 Jan;36(1):296-327

Thank You!!

Gram-negativeBacteria

TerlipressinTerlipressin

Vasopressin analogueVasopressin analogue Longer acting than vasopressin (halfLonger acting than vasopressin (half--life ~ 6 hours versus 6 life ~ 6 hours versus 6

minutes)minutes) Widely used inWidely used in EuropeEurope

UndergoingUndergoing trials in UStrials in US

UsesUses Shock associated with sepsis and other systemic inflammatory Shock associated with sepsis and other systemic inflammatory

processesprocesses

Potential problemsPotential problems Decreased cardiac outputDecreased cardiac output