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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

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Page 1: Vasopressors Judith Hellman, M.D. Associate ... Vasopressors.pdf · VasopressorsVasopressors Judith Hellman, M.D.Judith Hellman, M.D. Associate ProfessorAssociate Professor Anesthesia

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

Page 2: Vasopressors Judith Hellman, M.D. Associate ... Vasopressors.pdf · VasopressorsVasopressors Judith Hellman, M.D.Judith Hellman, M.D. Associate ProfessorAssociate Professor Anesthesia

OverviewOverviewDefine shock statesDefine shock statesReview drugs commonly used to treat hypotensionReview drugs commonly used to treat hypotensionOverview of drug management of shock statesOverview of drug management of shock statesDescribe 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 shockshockEuropean study European study -- Epinephrine Epinephrine vs Norepinephrine vs Norepinephrine + + dobutaminedobutaminePortuguese Study Portuguese Study -- Dopamine versus Dopamine versus NorepinephrineNorepinephrine

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Shock StatesShock StatesCardiogenicCardiogenicHypovolemic 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 ASObstruction of inflow Obstruction of inflow -- Cardiac Cardiac tamponadetamponade, , pneumothoraxpneumothorax

Medication effectsMedication effectsNeuraxial Neuraxial local anestheticslocal anestheticsSystemically 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 processesAcute adrenal insufficiencyAcute adrenal insufficiencyNeurogenic Neurogenic shockshock

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

Adrenergic AgentsAdrenergic Agents

PhenylephrinePhenylephrineNorepinephrineNorepinephrineEpinephrineEpinephrineDopamineDopamineDobutamineDobutamineIsoproterenolIsoproterenol

VasopressinVasopressin

β

α

α β1 β2

+++ − −

+++ ++ +

+++ +++ ++

++ ++ +

+ +++ +

− +++ +++

Page 5: Vasopressors Judith Hellman, M.D. Associate ... Vasopressors.pdf · VasopressorsVasopressors Judith Hellman, M.D.Judith Hellman, M.D. Associate ProfessorAssociate Professor Anesthesia

PhenylephrinePhenylephrineReceptors: Receptors: ααVascular effects: Vascular effects: Potent vasoconstrictorPotent vasoconstrictorCardiac effectsCardiac effects -- ReflexReflex

BradycardiaBradycardiaDecreased cardiac outputDecreased cardiac output

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

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NorepinephrineNorepinephrineReceptors: Receptors: αα and and β1, β1, minimal minimal β2 β2 -- α > βα > βVascular effects: Vascular effects: Potent vasoconstrictorPotent vasoconstrictorCardiac effectsCardiac effects

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

UsesUsesCombined Combined vasodilation vasodilation and myocardial dysfunctionand myocardial dysfunctionSepsis/SIRSSepsis/SIRS

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EpinephrineEpinephrineReceptors: Receptors: αα and and ββ -- α = βα = βVascular effects: Vascular effects: Potent vasoconstrictorPotent vasoconstrictorCardiac effectsCardiac effects

More potent effect on contractility than More potent effect on contractility than norepinephrinenorepinephrineIncreased heart rate/tachycardiaIncreased heart rate/tachycardia

UsesUsesWhen severe myocardial dysfunction is contributing to shockWhen severe myocardial dysfunction is contributing to shockCardiac arrest Cardiac arrest -- Can be givenCan be given intraintra--tracheallytracheallyAnaphylaxisAnaphylaxis

Potential ProblemsPotential ProblemsReduced Reduced splanchnic splanchnic blood flowblood flowIncreased myocardial work load Increased myocardial work load →→ ischemia, heart failureischemia, heart failure

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DopamineDopamineReceptors: Receptors: αα, , β1>β2, β1>β2, dopaminergicdopaminergicVascular effects: Vascular effects: Vasoconstricts Vasoconstricts at higher dosesat higher dosesCardiac effects Cardiac effects -- Lower dosesLower doses

Increased cardiac outputIncreased cardiac outputIncreased heart rateIncreased heart rate

UsesUsesShock from sepsis or other systemic inflammatory processesShock from sepsis or other systemic inflammatory processesTo increase urine output (low dose, To increase urine output (low dose, dopaminergic dopaminergic effect)effect)

Potential problemsPotential problemsDysrhythmias Dysrhythmias -- Atrial Atrial fibrillation,fibrillation, STSTNot a potent vasoconstrictor Not a potent vasoconstrictor -- oftenoften needneed additional additional pressorspressors

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DobutamineDobutamineReceptors: Receptors: ββ1> 1> ββ22CardiacCardiac effects: effects: ββ11

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

Vascular effects: Vascular effects: ββ2, 2, VasodilationVasodilationEffect on BP variableEffect on BP variableUsesUses

Cardiogenic Cardiogenic shockshockRefractory shock from sepsis or other systemic inflammatory Refractory shock from sepsis or other systemic inflammatory processprocess

Potential problemsPotential problemsTachydysrhythmiasTachydysrhythmiasHypotension can occur 2Hypotension can occur 2°° toto ββ2 effects2 effects

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VasopressinVasopressinHormone with many effects: vascular, renal, endocrineHormone with many effects: vascular, renal, endocrineVascularVascular

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

Vasopressin levels are decreased in sepsisVasopressin levels are decreased in sepsisUsesUses

Shock from sepsis and other inflammatory processes Shock from sepsis and other inflammatory processes -- Low dose Low dose PeriPeri--cardiopulmonary cardiopulmonary bypassbypassInstead ofInstead of epinephrine during epinephrine during cardiorespiratory cardiorespiratory arrestarrestHypotension due to ACE inhibitorHypotension due to ACE inhibitor

Potential problemsPotential problemsReduced GI blood flow, even atReduced GI blood flow, even at low doselow doseCardiac ischemiaCardiac ischemia

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Vasoactive Vasoactive Drug Management Drug Management of Shock Statesof Shock States

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Cardiogenic Cardiogenic ShockShock

Dobutamine Dobutamine NorephinephrineNorephinephrineEpinephrineEpinephrinePhosphdiesterase Phosphdiesterase inhibitors inhibitors -- Amrinone/milrinoneAmrinone/milrinone

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Hypovolemic Hypovolemic ShockShock

Fluid resuscitation!!Fluid resuscitation!!

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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 fluidsInotropes Inotropes or mixed or mixed inotrope/vasoconstrictor inotrope/vasoconstrictor -- dobutaminedobutamine, , norepinephrinenorepinephrine

Inflow problems Inflow problems -- Cardiac Cardiac tamponadetamponade, , pneumothoraxpneumothoraxFluidsFluidsRelieve sourceRelieve source ((pericardiocentesispericardiocentesis, chest tube), chest tube)

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MedicationMedication--Induced ShockInduced Shock

PathophysiologyPathophysiologyVasodilationVasodilationCardiac dysfunctionCardiac dysfunction

Neuraxial Neuraxial blockade blockade -- PhenylephrinePhenylephrineSystemic 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 dobutaminedobutamineConsider Consider norepinephrine norepinephrine if suspect concomitant if suspect concomitant vasodilationvasodilation

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Shock Associated with Systemic Shock Associated with Systemic Inflammatory ProcessInflammatory Process

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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:

NorephinephrineNorephinephrineDopamineDopamineVasopressinVasopressinPhenylephrinePhenylephrineDobutamineDobutamineEpinephrineEpinephrine

Physiology ofPhysiology of hypotension in systemic inflammatory hypotension in systemic inflammatory processesprocesses

Decreased vascular tone Decreased vascular tone →→ increased vascular capacitanceincreased vascular capacitanceDecreased myocardial contractilityDecreased myocardial contractility

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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 shockInclusion criteriaInclusion criteria

SIRS SIRS w/documented w/documented or suspected infectionor suspected infectionNE at NE at ≥≥ 5 5 μμg/ming/minNew 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 μμg/ming/minTitrate 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

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VASST: ResultsVASST: Results

Subjects Subjects -- 778 patients randomized778 patients randomizedVasopressinVasopressin 396396NE 382 NE 382

OutcomeOutcomeOverall 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 eventsSubgroups Subgroups

More severe More severe –– NE > 15mcg/min NE > 15mcg/min –– Higher mortality in Higher mortality in vasopressin groupvasopressin groupLess 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)

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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 NEPatients that are extremely Patients that are extremely acidemic acidemic so wonso 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 NEPatients on extremely high doses of NEACLS ACLS –– as an alternative to epinephrineas an alternative to epinephrinePeriPeri--CPBCPB

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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 ββ activityactivityStudy Design:Study Design: RandomizedRandomized trial of patients with septic shocktrial of patients with septic shockSubjects:Subjects: 330 patients randomized330 patients randomized

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

OutcomeOutcomeOverall 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 endpointsNoNo significant differences in serious adverse eventssignificant differences in serious adverse events

ConclusionsConclusionsNo significant differenceNo significant difference

Lancet. 2007 Aug 25;370(9588):676-84

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Dopamine: Dopamine: Sepsis Occurrence in Acutely Ill Patients (SOAP) Study

Hypothesis: Hypothesis: DA worsens outcome in shockStudy Design: Observational study in 198 ICUsStudy Design: Observational study in 198 ICUsSubjects: 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 NEDA: 35.4%; 8.8%%; 8.8% received only DAreceived only DAEpi: 23.3%; 4.5% only Epi: 23.3%; 4.5% only epiepiDobutamine Dobutamine + + catecholamines catecholamines 33.9%33.9%

OutcomeOutcomeDA and epinephrine used more in nonDA and epinephrine used more in non--survivorssurvivorsDADA 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 shock

Crit Care Med. 2006;34(3):589-97

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Portuguese Portuguese Community AcquiredSepsis Study :: Dopamine (DA) Dopamine (DA) vs vs NENEHypothesis: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 ICUsSubjects:Subjects: 458 patients with septic shock458 patients with septic shock

73% received NE73% received NE50.5% received DA50.5% received DA

OutcomeOutcomeNE associated with worse outcomeNE associated with worse outcomeNE 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

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Surviving Sepsis Campaign:Surviving Sepsis Campaign:2008 Guidelines2008 Guidelines

VasopressorsNE and DA are the initial vasopressors of choiceEpinephrine, phenylephrine, or vasopressin should not be administered as the initial vasopressor in septic shockVasopressin 0.03 units/min may be subsequently added to NEUse 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 therapyUse dobutamine in patients with myocardial dysfunction

Crit Care Med. 2008 Jan;36(1):296-327

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Thank You!!

Gram-negativeBacteria

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TerlipressinTerlipressin

Vasopressin analogueVasopressin analogueLonger 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 EuropeEuropeUndergoingUndergoing trials in UStrials in US

UsesUsesShock associated with sepsis and other systemic inflammatory Shock associated with sepsis and other systemic inflammatory processesprocesses

Potential problemsPotential problemsDecreased cardiac outputDecreased cardiac output