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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
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
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
Drugs Commonly Used to TreatDrugs Commonly Used to TreatShock in ICUsShock in ICUs
Adrenergic AgentsAdrenergic Agents
PhenylephrinePhenylephrineNorepinephrineNorepinephrineEpinephrineEpinephrineDopamineDopamineDobutamineDobutamineIsoproterenolIsoproterenol
VasopressinVasopressin
β
α
α β1 β2
+++ − −
+++ ++ +
+++ +++ ++
++ ++ +
+ +++ +
− +++ +++
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
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
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
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
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
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
Vasoactive Vasoactive Drug Management Drug Management of Shock Statesof Shock States
Cardiogenic Cardiogenic ShockShock
Dobutamine Dobutamine NorephinephrineNorephinephrineEpinephrineEpinephrinePhosphdiesterase 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 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)
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
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:
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
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
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)
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
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
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
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
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
Thank You!!
Gram-negativeBacteria
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