ShockShock

Division of Critical Care Division of Critical Care MedicineMedicine

University of AlbertaUniversity of Alberta

OUTLINEOUTLINE ClassificationClassification Common Pathways for ShockCommon Pathways for Shock Initial ManagementInitial Management CharacterizationCharacterization Mechanism of InotropyMechanism of Inotropy CatecholaminesCatecholamines What’s Next?What’s Next?

SHOCKSHOCKA syndrome A syndrome

characterized by characterized by inadequate cellular inadequate cellular

oxygen delivery with oxygen delivery with widespread organ widespread organ

damage and damage and dysfunction.dysfunction.

CLASSIFICATIONCLASSIFICATION HYPODYNAMICHYPODYNAMIC

CardiogenicCardiogenic HypovolemicHypovolemic ObstructiveObstructive

HYPERDYNAMICHYPERDYNAMIC DistributiveDistributive

CARDIOGENIC SHOCKCARDIOGENIC SHOCK LV infarctionLV infarction RV infarctionRV infarction Valvular dysfunctionValvular dysfunction CardiomyopathyCardiomyopathy ArrhythmiasArrhythmias Dynamic outflow Dynamic outflow

obstructionobstruction

HYPOVOLEMICHYPOVOLEMIC May occur with fluid loss from any May occur with fluid loss from any

compartment.compartment.

Patients with diastolic dysfunction have Patients with diastolic dysfunction have marked preload dependence with extreme marked preload dependence with extreme sensitivity to volume status.sensitivity to volume status.

Ischemic and reperfusion injury cause Ischemic and reperfusion injury cause endothelial dysfunction and refractory endothelial dysfunction and refractory shock.shock.

OBSTRUCTIVE CAUSESOBSTRUCTIVE CAUSES Pulmonary embolismPulmonary embolism Cardiac tamponadeCardiac tamponade Aortic dissectionAortic dissection Tension pneumothoraxTension pneumothorax Auto PEEPAuto PEEP

DISTRIBUTIVE SHOCKDISTRIBUTIVE SHOCK SepsisSepsis AnaphylaxisAnaphylaxis NeurogenicNeurogenic Adrenal insufficiencyAdrenal insufficiency

WHATEVER THE ORIGINAL MODE OF WHATEVER THE ORIGINAL MODE OF SHOCK, DECOMPENSATION OCCURS SHOCK, DECOMPENSATION OCCURS

VIA COMMON PATHWAYSVIA COMMON PATHWAYS HypovolemiaHypovolemia VasodilatationVasodilatation Myocardial depressionMyocardial depression Mediator cascade activationsMediator cascade activations Microcirculatory dysfunctionMicrocirculatory dysfunction Impaired mitochondrial Impaired mitochondrial

respirationrespiration

HYPOVOLEMIAHYPOVOLEMIA Endothelial injury results in increased Endothelial injury results in increased

capillary permeability and diminished capillary permeability and diminished reflectance to albumin.reflectance to albumin.

Dilation of capacitance vessels leads to Dilation of capacitance vessels leads to venous pooling and reduction in mean venous pooling and reduction in mean systemic pressure.systemic pressure.

Translocation of fluid to body cavities Translocation of fluid to body cavities and the GI tract can occur very quickly.and the GI tract can occur very quickly.

VASODILATIONVASODILATION NO release after induction of iNOS.NO release after induction of iNOS.

Endothelial membrane hyperpolarizationEndothelial membrane hyperpolarization

Decreased adrenoreceptor sensitivityDecreased adrenoreceptor sensitivity

? norepinephrine inactivation by ? norepinephrine inactivation by

peroxynitriteperoxynitrite

Vasopressin deficiencyVasopressin deficiency

Relative cortisol deficiencyRelative cortisol deficiency

Vessel constriction dependent on ingress of Vessel constriction dependent on ingress of CaCa++ ++ through voltagethrough voltage dependent channels.dependent channels.

Activation of ATP sensitive KActivation of ATP sensitive K++ channels channels allows membrane hyperpolarization and allows membrane hyperpolarization and inactivates Cainactivates Ca++++ channels. channels.

MYOCARDIAL DEPRESSIONMYOCARDIAL DEPRESSION Biventricular dilation and hypocontractility Biventricular dilation and hypocontractility

typical of septic shock.typical of septic shock.

EF usually 30 - 40 % but may be much lower.EF usually 30 - 40 % but may be much lower.

Cytokine and NO mediated.Cytokine and NO mediated.

Troponin release marker for depression.Troponin release marker for depression.

Degree of dilation associated with survival Degree of dilation associated with survival

(more dilation, better prognosis).(more dilation, better prognosis).

MEDIATOR ACTIVATIONMEDIATOR ACTIVATION Infection directly activates innate immune Infection directly activates innate immune

mechanisms via TLRs.mechanisms via TLRs.

Other shock states indirectly do so Other shock states indirectly do so following ischemia / reperfusion injury or following ischemia / reperfusion injury or after bacterial translocation from the gut.after bacterial translocation from the gut.

Activation of nuclear factor-Activation of nuclear factor-b results in b results in cytokine transcription.cytokine transcription.

Elaboration of TNF and Interleukin 1 Elaboration of TNF and Interleukin 1 central to development of SIRS.central to development of SIRS.

MICROCIRCULATORY MICROCIRCULATORY DYSFUNCTIONDYSFUNCTION

VOLUNTEERVOLUNTEER SEPSISSEPSIS

MICROCIRCULATORY MICROCIRCULATORY DYSFUNCTIONDYSFUNCTION

Endothelial injury and loss of Endothelial injury and loss of autoregulationautoregulation

Leukocyte rolling and adherenceLeukocyte rolling and adherence DIC with fibrin strands and micro DIC with fibrin strands and micro

thrombithrombi Tissue edemaTissue edema Decreased capillary density and Decreased capillary density and

high flow shuntshigh flow shunts Impaired oxygen diffusionImpaired oxygen diffusion

MITOCHONDRIAL FAILUREMITOCHONDRIAL FAILURE Electron transport chain inhibited by NO and Electron transport chain inhibited by NO and

its metabolite peroxynitrite.its metabolite peroxynitrite.

Evidence of actual mitochondrial injury.Evidence of actual mitochondrial injury.

Responsible for declining VO2 in setting of Responsible for declining VO2 in setting of increased DO2.increased DO2.

Failure of cellular energetics may be key Failure of cellular energetics may be key factor in organ dysfunction.factor in organ dysfunction.

INITIAL MANAGEMENTINITIAL MANAGEMENT

Usually necessary to initiate Usually necessary to initiate resuscitation prior to a full assessment.resuscitation prior to a full assessment.

Don’t forget the ABCs.Don’t forget the ABCs.

Responses to resuscitative maneuvers Responses to resuscitative maneuvers give clues to cause of shock.give clues to cause of shock.

RESPIRATORYRESPIRATORY Encephalopathy may develop early requiring Encephalopathy may develop early requiring

the airway to be protected.the airway to be protected.

Hypoxemia and increased work of breathing Hypoxemia and increased work of breathing may develop insidiously.may develop insidiously.

Early intubation and ventilation will decrease Early intubation and ventilation will decrease O2 requirements and improve O2 transport.O2 requirements and improve O2 transport.

Adopt a “lung protective” strategy early in Adopt a “lung protective” strategy early in course of acute lung injury.course of acute lung injury.

VENOUS ACCESSVENOUS ACCESS Large bore peripheral IVs more effective for Large bore peripheral IVs more effective for

giving fluids rapidly.giving fluids rapidly. Large caliber dual lumen dialysis catheters Large caliber dual lumen dialysis catheters

most effective in setting of exsanguinating most effective in setting of exsanguinating hemorrhage.hemorrhage.

Central lines should preferably be placed Central lines should preferably be placed above diaphragm to allow monitoring of above diaphragm to allow monitoring of CVP and SvO2.CVP and SvO2.

Beware femoral catheter sheaths which are Beware femoral catheter sheaths which are easily displaced extravascularly as edema easily displaced extravascularly as edema progresses.progresses.

BP MEASUREMENTBP MEASUREMENT Sphygmomanometry maySphygmomanometry may b be inaccurate in the e inaccurate in the

vasodilated patient and difficult in the vasodilated patient and difficult in the constricted.constricted.

Radial arterial lines may read significantly below Radial arterial lines may read significantly below a central arterial pressure with vasoconstriction.a central arterial pressure with vasoconstriction.

Femoral arterial lines most accurate in phase of Femoral arterial lines most accurate in phase of active resuscitation but consider early relocation.active resuscitation but consider early relocation.

With severe atherosclerotic disease or dissection With severe atherosclerotic disease or dissection it may be impossible to measure an accurate BP.it may be impossible to measure an accurate BP.

CORRECTION OF HYPOTENSIONCORRECTION OF HYPOTENSION Myocardial ischemia may occur at low Myocardial ischemia may occur at low

pressures even with normal coronary anatomy.pressures even with normal coronary anatomy.

Potential for cerebral ischemia and watershed Potential for cerebral ischemia and watershed infarcts.infarcts.

Initial measure will usually be administration of Initial measure will usually be administration of volume challenge.volume challenge.

It may be necessary to use vasopressors in a It may be necessary to use vasopressors in a setting of recognized hypovolemia or setting of recognized hypovolemia or hemorrhage to correct profound hypotension.hemorrhage to correct profound hypotension.

ASSESSMENTASSESSMENT GOALSGOALS Establish cause to allow definitive therapy.Establish cause to allow definitive therapy.

Quantitate physiological derangements.Quantitate physiological derangements. Severity of myocardial depression, Severity of myocardial depression,

volume contraction and vasodilatation volume contraction and vasodilatation vary widely in septic patients.vary widely in septic patients.

Document adequacy of resuscitationDocument adequacy of resuscitation Restoration of normal vital signs often Restoration of normal vital signs often

not consistent with normal not consistent with normal hemodynamics or microcirculatory hemodynamics or microcirculatory function.function.

CHARACTERIZATIONCHARACTERIZATION

IS CARDIAC OUTPUT HIGH OR LOW?IS CARDIAC OUTPUT HIGH OR LOW?

IS THE HEART FULL?IS THE HEART FULL?

WHAT IS THE RESPONSE TO VOLUME?WHAT IS THE RESPONSE TO VOLUME?

WHAT IS THE RESPONSE TO WHAT IS THE RESPONSE TO INOTROPE?INOTROPE?

CLINICAL EXAMCLINICAL EXAM Peripheries cool and clammy or well Peripheries cool and clammy or well

perfused?perfused?

Pulses bounding or low volume ?Pulses bounding or low volume ?

Jugular veins flat or distended ?Jugular veins flat or distended ?

What is the response to leg raising ?What is the response to leg raising ?

Is there evidence of organ hypoperfusion ?Is there evidence of organ hypoperfusion ? oliguriaoliguria obtundationobtundation

HEMODYNAMIC MONITORINGHEMODYNAMIC MONITORING Increases ability to characterize shock with Increases ability to characterize shock with

knowledge of C.I. and S.V.R.I.knowledge of C.I. and S.V.R.I.

Allows measurement of oxygen delivery and Allows measurement of oxygen delivery and consumption.consumption.

However, filling pressures a poor surrogate However, filling pressures a poor surrogate for estimation of ventricular filling or preload.for estimation of ventricular filling or preload.

Useful monitoring tool in some circumstances Useful monitoring tool in some circumstances but generally not shown to be of benefit.but generally not shown to be of benefit. ? inherently misleading? inherently misleading ? inadequate interpretation? inadequate interpretation ? ineffective interventions? ineffective interventions

ECHOCARDIOGRAPHY ECHOCARDIOGRAPHY Gives definitive diagnostic information in Gives definitive diagnostic information in

many circumstances.many circumstances.

Much more reliable guide to the adequacy Much more reliable guide to the adequacy of ventricular filling.of ventricular filling.

Should always be employed when invasive Should always be employed when invasive hemodynamic monitoring is being hemodynamic monitoring is being considered.considered.

Increasing availability of bedside Increasing availability of bedside technology.technology.

MIXED VENOUS OXIMETRYMIXED VENOUS OXIMETRY As oxygen extraction rises relative to DO2, As oxygen extraction rises relative to DO2,

SvO2 falls.SvO2 falls.

Low SvO2 correlates with inadequate Low SvO2 correlates with inadequate global DO2 and tissue hypoxia.global DO2 and tissue hypoxia.

Normal SvO2 does not exclude areas of Normal SvO2 does not exclude areas of regional ischemia.regional ischemia.

Measurements by intermittent sampling or Measurements by intermittent sampling or reflectance oximetry.reflectance oximetry.

Use as a guide for response to therapy.Use as a guide for response to therapy.

ARTERIAL LACTATEARTERIAL LACTATE Multiple causes of increased lactate in Multiple causes of increased lactate in

sepsis.sepsis. Tissue ischemiaTissue ischemia Hepatic hypoperfusion or failureHepatic hypoperfusion or failure Increased alanine metabolism “Cori cycle”Increased alanine metabolism “Cori cycle” Inhibition of pyruvate dehydrogenaseInhibition of pyruvate dehydrogenase

Elevation of lactate > 2mmol/L a marker for Elevation of lactate > 2mmol/L a marker for increased mortality and its failure to fall increased mortality and its failure to fall with Rx more strongly so.with Rx more strongly so.

GASTRIC TONOMETRYGASTRIC TONOMETRY Saline filled gastric balloon equilibrates with Saline filled gastric balloon equilibrates with

gastric mucosal pCO2.gastric mucosal pCO2.

Impaired tissue perfusion leads to Impaired tissue perfusion leads to accumulation of tissue pCO2 and increasing accumulation of tissue pCO2 and increasing gap between tissue and arterial pCO2.gap between tissue and arterial pCO2.

Correlates with other evidence for tissue Correlates with other evidence for tissue hypoxia and with outcome.hypoxia and with outcome.

Expensive and unwieldy.Expensive and unwieldy. Limited improvement in discrimination Limited improvement in discrimination

compared to lactate levels.compared to lactate levels.

RESEARCH TOOLSRESEARCH TOOLS Direct measurement tissue pO2.Direct measurement tissue pO2.

Near infrared spectroscopy.Near infrared spectroscopy. Redox state of cytochrome oxidaseRedox state of cytochrome oxidase

Luminescent oxygen probesLuminescent oxygen probes Redox state of NADHRedox state of NADH

MicrodialysisMicrodialysis tissue lactatetissue lactate

PET scanningPET scanning ATP levelsATP levels

MANAGEMENT GOALSMANAGEMENT GOALS Normalize vital signs.Normalize vital signs. Normalize global O2 transport.Normalize global O2 transport. Eliminate evidence of tissue dysoxia.Eliminate evidence of tissue dysoxia.

Definitive Rx of cause:Definitive Rx of cause: Source control and antibiotics in sepsisSource control and antibiotics in sepsis Thrombolysis of PEThrombolysis of PE PCI in MIPCI in MI

Organ protective strategiesOrgan protective strategies

OPTIMIZE PRELOADOPTIMIZE PRELOAD Fundamental to any resuscitation strategyFundamental to any resuscitation strategy

FLUID CHALLENGES MUST BE OF ADEQUATE FLUID CHALLENGES MUST BE OF ADEQUATE VOLUME , BE INFUSED RAPIDLY AND THE VOLUME , BE INFUSED RAPIDLY AND THE EFFECTS OBSERVED IMMEDIATELYEFFECTS OBSERVED IMMEDIATELY

Monitoring of response to volume challengeMonitoring of response to volume challenge ClinicallyClinically Hemodynamic parametersHemodynamic parameters EchocardiographicallyEchocardiographically

CHOICE OF FLUIDCHOICE OF FLUID No evidence of increased efficacy of albumin No evidence of increased efficacy of albumin

compared to crystalloid solutions.compared to crystalloid solutions.

Limited trials of non albumin colloids (i.e. Limited trials of non albumin colloids (i.e. Pentaspan).Pentaspan).

Large volumes of N/S contribute to metabolic Large volumes of N/S contribute to metabolic acidosis.acidosis.

Pentaspan contributes to coagulopathy in large Pentaspan contributes to coagulopathy in large volumes or in already coagulopathic patients.volumes or in already coagulopathic patients.

Some evidence of improved efficacy with Some evidence of improved efficacy with hypertonic saline solutions.hypertonic saline solutions.

? OPTIMAL HEMATCRIT? OPTIMAL HEMATCRIT Transfused blood recognized to be Transfused blood recognized to be

immunosuppressive and to independently immunosuppressive and to independently contribute to mortality.contribute to mortality.

Limitation of oxygen carrying capacity of Limitation of oxygen carrying capacity of stored RBCs due to low levels of 2,3 DPG.stored RBCs due to low levels of 2,3 DPG.

In absence of myocardial ischemia a In absence of myocardial ischemia a transfusion trigger of < 7g/l improved or transfusion trigger of < 7g/l improved or did not worsen outcome.did not worsen outcome.

In presence of lingering evidence of tissue In presence of lingering evidence of tissue hypoxia transfusion to Hb 10 g/l should be hypoxia transfusion to Hb 10 g/l should be considered.considered.

MECHANISMS OF MECHANISMS OF INOTROPYINOTROPY

DIFFERENTIAL DIFFERENTIAL RESPONSIVENESSRESPONSIVENESS

The effects of any vasoactive agent may be The effects of any vasoactive agent may be quite different depending on numerous quite different depending on numerous premorbid and postmorbid considerations.premorbid and postmorbid considerations.

Pharmacokinetic as well as pharmacodynamic Pharmacokinetic as well as pharmacodynamic variation occurs.variation occurs.

Evidence of genetic polymorphism of receptor Evidence of genetic polymorphism of receptor populations and signal transduction systems.populations and signal transduction systems.

PREMORBID ISSUESPREMORBID ISSUES

DiabetesDiabetes HypertensionHypertension Hx of CHFHx of CHF Use of vasoactivesUse of vasoactives

PRELOADPRELOAD Development of tachycardia in response Development of tachycardia in response

to inotropes often indicative of low to inotropes often indicative of low preload.preload.

Absence of pressor response or active Absence of pressor response or active deterioration in response to inotropes deterioration in response to inotropes may result from dynamic left ventricular may result from dynamic left ventricular outflow tract obstruction (DLVOTO).outflow tract obstruction (DLVOTO).

DLVOTODLVOTO Anterior mitral valve leaflet impinges Anterior mitral valve leaflet impinges

on LVOT.on LVOT.

Results in MR and/or obstruction.Results in MR and/or obstruction.

Classically found in HOCM.Classically found in HOCM.

Common occurrence in setting of LVH Common occurrence in setting of LVH and under filling.and under filling.

INOTROPY IN ENDOTHELIAL INOTROPY IN ENDOTHELIAL INJURYINJURY

Ischemia / reperfusion injury.Ischemia / reperfusion injury. Massive endothelial apoptosis Massive endothelial apoptosis

associated with sepsis.associated with sepsis.

Loss of autoregulation.Loss of autoregulation. Paradoxical responses.Paradoxical responses. Diminished catecholamine metabolism.Diminished catecholamine metabolism.

ALTERED KINETICSALTERED KINETICS Significant metabolism of norepinephrine Significant metabolism of norepinephrine

and dopamine in the lung.and dopamine in the lung.

Dopamine most prone to variable Dopamine most prone to variable kinetics particularly with combined kinetics particularly with combined hepatic and renal dysfunction.hepatic and renal dysfunction.

Milrinone is renal excreted with markedly Milrinone is renal excreted with markedly prolonged half-life in renal failure and prolonged half-life in renal failure and unknown kinetics on CVVHD.unknown kinetics on CVVHD.

The number of receptor subtypes The number of receptor subtypes seems to be creeping up with ever seems to be creeping up with ever more complex interactions.more complex interactions.

RECEPTOR POPULATIONSRECEPTOR POPULATIONS

CHF associated with change in CHF associated with change in number and type of receptors.number and type of receptors.

Decreased numbers of Decreased numbers of 1 receptors1 receptors Increased expression of Increased expression of 3 receptors3 receptors Increased expression of Increased expression of 1 receptors1 receptors

ALTERED G PROTEIN ALTERED G PROTEIN COUPLINGCOUPLING

Most vasoactive agents activate G protein Most vasoactive agents activate G protein coupled receptors (GPCR).coupled receptors (GPCR).

Increased substitution of GIncreased substitution of Gi subunit into i subunit into heterotrimer causing decreased responsiveness.heterotrimer causing decreased responsiveness.

Overexpression of GOverexpression of Gi in sepsis.i in sepsis.

Stimulated by increased NO production.Stimulated by increased NO production.

PATHWAYS FOR RECEPTOR PATHWAYS FOR RECEPTOR DESENSITIZATIONDESENSITIZATION

Phosphorylation by GPCR kinase and Phosphorylation by GPCR kinase and subsequent internalization linked to subsequent internalization linked to receptor activation.receptor activation.

Phosphorylation by serine / threonine Phosphorylation by serine / threonine kinases not linked to receptor activation.kinases not linked to receptor activation.

SECOND MESSENGER SECOND MESSENGER GENERATIONGENERATION

Phospholipase CPhospholipase C Adenyl cyclaseAdenyl cyclase NOSNOS Guanylate cyclaseGuanylate cyclase

All subject to polymorphism All subject to polymorphism and multiple control systemsand multiple control systems

CORTISOLCORTISOL Increases transcription and expression of Increases transcription and expression of

adrenergic receptors.adrenergic receptors.

Required for synthesis of catecholamines.Required for synthesis of catecholamines.

Reduces transcription of iNOS.Reduces transcription of iNOS.

True and relative cortisol deficiency seems True and relative cortisol deficiency seems common in sepsis.common in sepsis.

CATECHOLAMINESCATECHOLAMINES

NOREPINEPHRINENOREPINEPHRINE Potent Potent 1 agonist equivalent to epinephrine.1 agonist equivalent to epinephrine.

Potent Potent 1 agonist.1 agonist.

Lacks Lacks 2 agonism therefore unopposed 2 agonism therefore unopposed vasoconstriction.vasoconstriction.

Also has Also has 2 activity which may limit 2 activity which may limit splanchnic blood flow.splanchnic blood flow.

EPINEPHRINEEPINEPHRINE Potent Potent 1 and 1 and 1 agonist.1 agonist.

Potent Potent 2 agonist therefore increased 2 agonist therefore increased muscle blood flow.muscle blood flow.

Marked metabolic effects with major Marked metabolic effects with major increase in lactate production.increase in lactate production.

Demonstrated to promote GI ischemia.Demonstrated to promote GI ischemia.

DOPAMINEDOPAMINE Direct Direct 1 effects.1 effects.

Indirect effects due to peripheral Indirect effects due to peripheral release of norepinephrine.release of norepinephrine.

Highly variable often exhibiting Highly variable often exhibiting significant significant 1 activity at low doses.1 activity at low doses.

The triphasic response described in the The triphasic response described in the

texts is fictional in clinical practice.texts is fictional in clinical practice.

Low dose dopamine causes dilation of Low dose dopamine causes dilation of efferent and afferent renal arterioles and efferent and afferent renal arterioles and significant increase in renal blood flow significant increase in renal blood flow without impact on glomerular pressure without impact on glomerular pressure or GFR in the normal kidney.or GFR in the normal kidney.

In sepsis changes in renal blood flow due In sepsis changes in renal blood flow due to changes in perfusion pressure only.to changes in perfusion pressure only.

Impairs solute reabsorption proximally Impairs solute reabsorption proximally and may promote diuresis.and may promote diuresis.

Profound effects on anterior pituitary Profound effects on anterior pituitary function.function.

PHENYLEPHRINEPHENYLEPHRINE Pure Pure 1 agonist1 agonist

May be inappropriate alone in setting of May be inappropriate alone in setting of myocardial depression and ventricular myocardial depression and ventricular dilatation.dilatation.

Useful when arrhythmias aggravated by Useful when arrhythmias aggravated by agonists.agonists.

Some evidence that the absence of Some evidence that the absence of 2 2 activity may preserve splanchnic blood activity may preserve splanchnic blood flow.flow.

VASOPRESSIN VASOPRESSIN

VASOPRESSIN IN SHOCKVASOPRESSIN IN SHOCK Little role in blood pressure control normally.Little role in blood pressure control normally.

Vasodilatory actions in some tissue beds.Vasodilatory actions in some tissue beds.

Profound increase with onset of shock of all kinds.Profound increase with onset of shock of all kinds.

High levels maintained in cardiogenic shock but High levels maintained in cardiogenic shock but drop quickly in sepsis to physiologic levels.drop quickly in sepsis to physiologic levels.

Cause of drop uncertain but some evidence of Cause of drop uncertain but some evidence of depletion of neurohypophysis.depletion of neurohypophysis.

Low levels early in shock predictive of refractory Low levels early in shock predictive of refractory hypotension.hypotension.

VASOPRESSINVASOPRESSIN Extreme sensitivity to small doses in sepsis.Extreme sensitivity to small doses in sepsis.

Usual dose range 0.01 - 0.04 Us / min.Usual dose range 0.01 - 0.04 Us / min.

Consistently increases MAP and usually increases Consistently increases MAP and usually increases U.O.U.O.

Concern re effects on splanchnic blood flow but Concern re effects on splanchnic blood flow but little evidence of reduced flow in experimental little evidence of reduced flow in experimental models or clinically.models or clinically.

Superior to norepinephrine in most models.Superior to norepinephrine in most models.

No hard outcome data as yet.No hard outcome data as yet.

Used as 2nd line agent to decrease norepi Used as 2nd line agent to decrease norepi dependence.dependence.

DOBUTAMINEDOBUTAMINE Racemic mixtureRacemic mixture

(+) enantiomer activates (+) enantiomer activates 1 and 21 and 2

(-) enantiomer activates (-) enantiomer activates 1 receptors1 receptors

Usually behaves as pure inotrope but occasionally Usually behaves as pure inotrope but occasionally exhibits significant peripheral effects.exhibits significant peripheral effects.

Some evidence of microcirculatory recruitment Some evidence of microcirculatory recruitment unrelated to systemic hemodynamics.unrelated to systemic hemodynamics.

MILRINONEMILRINONE Inhibits PDE III increasing cAMP levels.Inhibits PDE III increasing cAMP levels. Independent of Independent of receptor. receptor. Potent inotrope and vasodilator.Potent inotrope and vasodilator. Less arrythmogenic than Less arrythmogenic than agonists. agonists.

May be used alone or in combination with other May be used alone or in combination with other inotropes.inotropes.

Often requires Often requires agonists or vasopressin agonists or vasopressin to to control vasodilatation.control vasodilatation.

LEVOSIMENDANLEVOSIMENDAN Calcium sensitizing agentCalcium sensitizing agent

Hemodynamic profile similar to milrinone Hemodynamic profile similar to milrinone with significant peripheral dilationwith significant peripheral dilation

Compares favorably with dobutamine in heart Compares favorably with dobutamine in heart failure (LIDO trial).failure (LIDO trial).

Favorable reports in sepsis.Favorable reports in sepsis.

? SUPRANORMAL DO2? SUPRANORMAL DO2 Patients who spontaneously achieve high Patients who spontaneously achieve high

levels of DO2 have better outcomes.levels of DO2 have better outcomes.

Trials using therapies to achieve similar levels Trials using therapies to achieve similar levels of DO2 have not consistently demonstrated of DO2 have not consistently demonstrated improved outcomes.improved outcomes.

Current approach not to target high DO2 in the Current approach not to target high DO2 in the absence of lingering signs of tissue hypoxia.absence of lingering signs of tissue hypoxia.

Demonstrated that early Demonstrated that early resuscitation of the septic patient resuscitation of the septic patient using SvO2 or ScvO2 as an endpoint using SvO2 or ScvO2 as an endpoint for adequacy of global oxygen for adequacy of global oxygen delivery produced a marked delivery produced a marked improvement in outcome.improvement in outcome.

WHATS NEXT?WHATS NEXT?

RESUSCITATION OF THE RESUSCITATION OF THE MICROCIRCULATIONMICROCIRCULATION

Techniques now developed for visualizing and Techniques now developed for visualizing and investigating the microcirculation.investigating the microcirculation.

Some vasodilators lead to recruitment but adverse Some vasodilators lead to recruitment but adverse effects on systemic hemodynamics.effects on systemic hemodynamics.

rAPC may have its major beneficial effect by rAPC may have its major beneficial effect by preventing leukocyte adherence and obstruction.preventing leukocyte adherence and obstruction.

N-acetylcysteine may have similar effects and act N-acetylcysteine may have similar effects and act as a microcirculatory dilator.as a microcirculatory dilator.

RESUSCITATION OF RESUSCITATION OF MITOCHONDRIAL RESPIRATIONMITOCHONDRIAL RESPIRATION

Will enhanced antioxidant defenses be of Will enhanced antioxidant defenses be of benefit?benefit?

Will enhanced substrate flow maintain Will enhanced substrate flow maintain energetics?energetics?

Will stimulation of mitochondrial activity with Will stimulation of mitochondrial activity with leptin lead to earlier return of organ leptin lead to earlier return of organ functions?functions?

Will we routinely be monitoring the electron Will we routinely be monitoring the electron transport chain with NADH fluometry and NIR?transport chain with NADH fluometry and NIR?

SUMMARYSUMMARY ClassificationClassification Common Pathways for ShockCommon Pathways for Shock Initial ManagementInitial Management CharacterizationCharacterization Mechanism of InotropyMechanism of Inotropy CatecholaminesCatecholamines What’s Next?What’s Next?