PressorsPressors

Scott Forman, D.O.Scott Forman, D.O.

Adrenergic Receptor PhysiologyAdrenergic Receptor Physiology

Alpha-1Alpha-1 Beta-1Beta-1 Beta-2Beta-2 DopamineDopamine

Alpha Adrenergic ReceptorsAlpha Adrenergic Receptors

Located in vascular wallsLocated in vascular walls– Induces significant vasoconstrictionInduces significant vasoconstriction

Present in heartPresent in heart– Increase the duration of the contraction without Increase the duration of the contraction without

increased chronotropy.increased chronotropy.

Beta Adrenergic ReceptorsBeta Adrenergic Receptors

Beta-1 adrenergic receptors are most Beta-1 adrenergic receptors are most common in the heartcommon in the heart– Mediate increases in inotropy and chronotropy Mediate increases in inotropy and chronotropy

with minimal vasoconstriction.with minimal vasoconstriction. Beta-2 adrenergic receptors in blood vessels Beta-2 adrenergic receptors in blood vessels

induce vasodilation.induce vasodilation.

Dopamine ReceptorsDopamine Receptors

Present in the renal, splanchnic, coronary, Present in the renal, splanchnic, coronary, and cerebral vascular beds.and cerebral vascular beds.

Stimulation of these receptors leads to Stimulation of these receptors leads to vasodilation.vasodilation.

Second subtype of dopamine receptors Second subtype of dopamine receptors causes vasoconstriction by inducing causes vasoconstriction by inducing norepinephrine releasenorepinephrine release

Principles Of Use Of Principles Of Use Of Vasopressors and InotropesVasopressors and Inotropes

Hypotension may result from:Hypotension may result from:– HypovolemiaHypovolemia– Pump failurePump failure– Pathologic maldistribution of blood flowPathologic maldistribution of blood flow

Vasopressors are indicated for:Vasopressors are indicated for:– Decrease of >30 mmHg from baseline SBP orDecrease of >30 mmHg from baseline SBP or– MAP <60 mmHg andMAP <60 mmHg and– Evidence of end-organ dysfunction due to Evidence of end-organ dysfunction due to

hypoperfusionhypoperfusion Hypovolemia must be corrected firstHypovolemia must be corrected first

Principles Of Use Of Principles Of Use Of Vasopressors and Inotropes Vasopressors and Inotropes

Use of vasopressors and inotropes is guided Use of vasopressors and inotropes is guided by three fundamental concepts:by three fundamental concepts:– One drug, many receptorsOne drug, many receptors– Dose-response curveDose-response curve– Direct versus reflex actionsDirect versus reflex actions

Volume ResuscitationVolume Resuscitation

Repletion of adequate intravascular volume, Repletion of adequate intravascular volume, when time permits, is crucial prior to the when time permits, is crucial prior to the initiation of vasopressors.initiation of vasopressors.– Vasopressors will be ineffective or only Vasopressors will be ineffective or only

partially effective in the setting of coexisting partially effective in the setting of coexisting hypovolemia.hypovolemia.

Fluids may be withheld in patients with Fluids may be withheld in patients with significant pulmonary edema due to ARDS significant pulmonary edema due to ARDS or CHF.or CHF.

Selection and TitrationSelection and Titration

Choice of an initial agent should be based Choice of an initial agent should be based upon the suspected underlying etiology of upon the suspected underlying etiology of shock.shock.

Dose should be titrated up to achieve Dose should be titrated up to achieve effective BP or end-organ perfusion.effective BP or end-organ perfusion.

If maximal doses of a first agent are If maximal doses of a first agent are inadequate, then a second drug should be inadequate, then a second drug should be added to the first.added to the first.

TachyphylaxisTachyphylaxis

Responsiveness to these drugs can decrease Responsiveness to these drugs can decrease over time due to tachyphylaxis.over time due to tachyphylaxis.

Doses must be constantly titrated to adjust Doses must be constantly titrated to adjust for this phenomenon and for changes in the for this phenomenon and for changes in the patients clinical condition.patients clinical condition.

Subcutaneous Drug DeliverySubcutaneous Drug Delivery

Bioavailability of subcutaneous heparin or Bioavailability of subcutaneous heparin or insulin can be reduced during treatment insulin can be reduced during treatment with vasopressors due to cutaneous with vasopressors due to cutaneous vasoconstriction.vasoconstriction.

Phenylephrine (Neosynephrine)Phenylephrine (Neosynephrine)

Purely alpha-adrenergic agonist activityPurely alpha-adrenergic agonist activity– Vasoconstriction with minimal cardiac inotropy Vasoconstriction with minimal cardiac inotropy

or chronotropy.or chronotropy. Useful in settings of hypotension with SVR Useful in settings of hypotension with SVR

< 700 dynes x sec/cm5< 700 dynes x sec/cm5– Hyperdynamic sepsis, neurologic disorders, Hyperdynamic sepsis, neurologic disorders,

anesthesia induced hypotension.anesthesia induced hypotension. Contraindicated if SVR > 1200 dynes x Contraindicated if SVR > 1200 dynes x

sec/cm5sec/cm5

Norepinephrine (Levophed)Norepinephrine (Levophed)

Acts on both alpha-1 and beta-1 receptorsActs on both alpha-1 and beta-1 receptors– Potent vasoconstriction as well as a less Potent vasoconstriction as well as a less

pronounced increase in cardiac outputpronounced increase in cardiac output Reflex bradycardia usually occurs in Reflex bradycardia usually occurs in

response to the increased MAPresponse to the increased MAP– Mild chronotropic effect is cancelled out and Mild chronotropic effect is cancelled out and

the HR remains unchanged or decreases the HR remains unchanged or decreases slightly.slightly.

Used most commonly to treat septic shock.Used most commonly to treat septic shock.

Epinephrine (Adrenalin)Epinephrine (Adrenalin)

Potent beta-1 receptor activity and moderate beta-Potent beta-1 receptor activity and moderate beta-2 and alpha-1 receptor effects.2 and alpha-1 receptor effects.

Result is an increased CO, with decreased SVR Result is an increased CO, with decreased SVR and variable effects on the MAP.and variable effects on the MAP.

Beta-1 receptor stimulation may provoke Beta-1 receptor stimulation may provoke dysrhythmias.dysrhythmias.

Greater degree of splanchnic vasoconstriction.Greater degree of splanchnic vasoconstriction. Most often used in treatment of anaphylaxis, as a Most often used in treatment of anaphylaxis, as a

second line agent in septic shock and for second line agent in septic shock and for management of hypotension following CABG.management of hypotension following CABG.

Dopamine (Intropin)Dopamine (Intropin)

At low doses, dopamine acts predominately on At low doses, dopamine acts predominately on dopamine-1 receptors in the renal mesenteric, dopamine-1 receptors in the renal mesenteric, cerebral, and coronary beds, resulting in selective cerebral, and coronary beds, resulting in selective vasodilation.vasodilation.

At moderate doses, dopamine also stimulates At moderate doses, dopamine also stimulates Beta-1 receptors and increases CO, predominately Beta-1 receptors and increases CO, predominately by increasing SV with variable effects on HR.by increasing SV with variable effects on HR.– Can result in dose-limiting dysrhythmiasCan result in dose-limiting dysrhythmias

At higher doses, dopamine stimulates alpha At higher doses, dopamine stimulates alpha receptors and produces vasoconstriction with an receptors and produces vasoconstriction with an increased SVR.increased SVR.

Dopamine (Intropin)Dopamine (Intropin)

The dose-dependent effects of dopamine The dose-dependent effects of dopamine mean that increasing the dose of the drug is mean that increasing the dose of the drug is akin to switching vasopressors.akin to switching vasopressors.

Most often used in hypotension due to Most often used in hypotension due to sepsis or cardiac failuresepsis or cardiac failure

Dobutamine (Dobutrex)Dobutamine (Dobutrex)

Not a vasopressor but rather an inotrope that Not a vasopressor but rather an inotrope that causes vasodilation.causes vasodilation.

Predominant beta-1 receptor effect increases Predominant beta-1 receptor effect increases inotropy and chronotropy and reduces LV filling inotropy and chronotropy and reduces LV filling pressures.pressures.

Minimal alpha and beta-2 receptor effects result in Minimal alpha and beta-2 receptor effects result in overall vasodilation, complemented by reflex overall vasodilation, complemented by reflex vasodilation to the increased CO.vasodilation to the increased CO.

Net effect is increased CO, with decreased SVR Net effect is increased CO, with decreased SVR with or without a small reduction in BP.with or without a small reduction in BP.

Dobutamine (Dobutrex)Dobutamine (Dobutrex)

Frequently used in severe, medically Frequently used in severe, medically refractory heart failure and cardiogenic refractory heart failure and cardiogenic shock.shock.

Should not be routinely used in sepsis Should not be routinely used in sepsis because of the risk of hypotension.because of the risk of hypotension.

Does not selectively vasodilate the renal Does not selectively vasodilate the renal vascular bed.vascular bed.

Phosphodiesterase InhibitorsPhosphodiesterase Inhibitors

Amrinone and MilrinoneAmrinone and Milrinone Nonadrenergic drugs with inotropic and Nonadrenergic drugs with inotropic and

vasodilatory actions.vasodilatory actions. Effects are similar to dobutamine but with a Effects are similar to dobutamine but with a

lower incidence of dysrhythmias.lower incidence of dysrhythmias. Used to treat patients with impaired cardiac Used to treat patients with impaired cardiac

function and medically refractory HF.function and medically refractory HF. Vasodilatory properties limit their use in Vasodilatory properties limit their use in

hypotensive patients.hypotensive patients.

VasopressinVasopressin

Usually used in the setting of DI or esophageal Usually used in the setting of DI or esophageal variceal bleeding.variceal bleeding.

May be useful in the treatment of refractory septic May be useful in the treatment of refractory septic shock, particularly as a second pressor agent.shock, particularly as a second pressor agent.

Studies showed that the addition of vasopressin to Studies showed that the addition of vasopressin to norepinephrine was more effective in reversing norepinephrine was more effective in reversing late vasodilatory shock than norepinephrine alone.late vasodilatory shock than norepinephrine alone.

Complications include coronary and mesenteric Complications include coronary and mesenteric ischemia, hyponatremia, pulmonary ischemia, hyponatremia, pulmonary vasoconstriction, and skin necrosis from vasoconstriction, and skin necrosis from peripheral infusion.peripheral infusion.

ComplicationsComplicationsHypoperfusionHypoperfusion

Commonly occurs in the setting of Commonly occurs in the setting of inadequate cardiac output or inadequate inadequate cardiac output or inadequate volume resuscitation.volume resuscitation.

Dusky skin changes at the tips of the fingers Dusky skin changes at the tips of the fingers and toes, renal insufficiency and oliguria, and toes, renal insufficiency and oliguria, and possible limb ischemia.and possible limb ischemia.

Increase the risk of gastritis, shock liver, Increase the risk of gastritis, shock liver, intestinal ischemia, or translocation of gut intestinal ischemia, or translocation of gut flora with resultant bacteremia.flora with resultant bacteremia.

ComplicationsComplicationsDysrhythmiasDysrhythmias

Stimulation of beta-1 receptors.Stimulation of beta-1 receptors. Increases the risk of sinus tachycardia, atrial Increases the risk of sinus tachycardia, atrial

fibrillation, AVnRT, or ventricular fibrillation, AVnRT, or ventricular tachyarrhythmias.tachyarrhythmias.

Limit the maximal dose and necessitate Limit the maximal dose and necessitate switching to another agent with less switching to another agent with less prominent beta-1 effects.prominent beta-1 effects.

ComplicationsComplicationsMyocardial ischemiaMyocardial ischemia

Beta receptor stimulation can increase Beta receptor stimulation can increase myocardial oxygen consumption.myocardial oxygen consumption.

Excessive tachycardia should be avoided Excessive tachycardia should be avoided because of impaired diastolic filling of the because of impaired diastolic filling of the coronary arteries.coronary arteries.

ComplicationsComplicationsLocal effectsLocal effects

Peripheral extravasation of vasopressors Peripheral extravasation of vasopressors into the surrounding connective tissue can into the surrounding connective tissue can lead to excessive local vasoconstriction lead to excessive local vasoconstriction with subsequent skin necrosis.with subsequent skin necrosis.

Vasopressors should be administered via a Vasopressors should be administered via a central line.central line.

Local treatment with phentolamine (5 – Local treatment with phentolamine (5 – 10mg) sub-Q can minimize local 10mg) sub-Q can minimize local vasoconstriction.vasoconstriction.

ComplicationsComplicationsHyperglycemiaHyperglycemia

May occur due to inhibition of insulin May occur due to inhibition of insulin secretion.secretion.

Magnitude of hyperglycemia generally is Magnitude of hyperglycemia generally is mild.mild.

More pronounced with norepinephrine and More pronounced with norepinephrine and epinephrine than dopamine.epinephrine than dopamine.

Drug interactions/ Drug interactions/ ContraindicationsContraindications

Patients with pheochromocytoma are at risk Patients with pheochromocytoma are at risk of excessive autonomic stimulation from of excessive autonomic stimulation from pressors.pressors.

Dobutamine is contraindicated in the setting Dobutamine is contraindicated in the setting of IHSS.of IHSS.

Patients receiving monoamine oxidase Patients receiving monoamine oxidase inhibitors are extremely sensitive to inhibitors are extremely sensitive to pressors, and require much lower doses.pressors, and require much lower doses.

““Renal-dose” DopamineRenal-dose” Dopamine

Dopamine selectively increases renal blood Dopamine selectively increases renal blood flow when administered at 1-3 mcg/kg/minflow when administered at 1-3 mcg/kg/min

Currently, there is no data to support the Currently, there is no data to support the routine use of low dose dopamine to routine use of low dose dopamine to prevent or treat acute renal failure or prevent or treat acute renal failure or mesenteric ischemia.mesenteric ischemia.

Vasopressor Use in Septic ShockVasopressor Use in Septic Shock

Patients with hyperdynamic septic shock Patients with hyperdynamic septic shock (hypotension, low SVR, and high CI) tend to have (hypotension, low SVR, and high CI) tend to have warm extremities due to inappropriate warm extremities due to inappropriate hyperperfusion of the skin and soft tissues.hyperperfusion of the skin and soft tissues.– Norepinephrine and phenylephrine appear more potent Norepinephrine and phenylephrine appear more potent

in hyperdynamic sepsis.in hyperdynamic sepsis. Patients with hypodynamic septic shock Patients with hypodynamic septic shock

(hypotension, low SVR, and low CI) manifest (hypotension, low SVR, and low CI) manifest hypoperfusion of the extremities.hypoperfusion of the extremities.– Dopamine may be preferable in patients with Dopamine may be preferable in patients with

hypodynamic sepsis.hypodynamic sepsis.

Management of Septic ShockManagement of Septic Shock

Scott Forman, D.O.Scott Forman, D.O.

IntroductionIntroduction

Over 750,00 cases of sepsis occur in the Over 750,00 cases of sepsis occur in the U.S. each yearU.S. each year

Approximately 200,000 fatalitiesApproximately 200,000 fatalities Unfortunately, even with optimal treatment, Unfortunately, even with optimal treatment,

the mortality rate from severe sepsis or the mortality rate from severe sepsis or septic shock is approximately 40% .septic shock is approximately 40% .

Therapeutic PrioritiesTherapeutic Priorities

First priority is to employ supportive measures First priority is to employ supportive measures that counter physiologic abnormalities such as that counter physiologic abnormalities such as hypoxemia, hypotension, and impaired tissue hypoxemia, hypotension, and impaired tissue oxygenation.oxygenation.

Early efforts must determine if SIRS is due to a Early efforts must determine if SIRS is due to a noninfectious cause or is the result of an infection.noninfectious cause or is the result of an infection.

Identifying that infection is the cause of SIRS and Identifying that infection is the cause of SIRS and finding the source are critical early priorities.finding the source are critical early priorities.

Patient must be assessed for adequate tissue Patient must be assessed for adequate tissue perfusion.perfusion.

Initial ManagementInitial Management

ResuscitationResuscitation Supportive careSupportive care MonitoringMonitoring Targeted antimicrobial therapyTargeted antimicrobial therapy Drainage for infectionDrainage for infection

ResuscitationResuscitation

The first step in the management of the The first step in the management of the patient with septic shack is to assess the patient with septic shack is to assess the ABC’s.ABC’s.

Supplemental oxygen should be supplied to Supplemental oxygen should be supplied to all patients with sepsis.all patients with sepsis.

The next priority is to assist ventilation and The next priority is to assist ventilation and augment oxygenation.augment oxygenation.

Then, measures are taken to restore the BP Then, measures are taken to restore the BP to levels that perfuse vital organs.to levels that perfuse vital organs.

Monitoring of Tissue PerfusionMonitoring of Tissue Perfusion

Circulatory failure is present by definition Circulatory failure is present by definition in patients with septic shock.in patients with septic shock.

The sphygmomanometer may be unreliable The sphygmomanometer may be unreliable in hypotensive patients.in hypotensive patients.

An arterial catheter may be inserted if blood An arterial catheter may be inserted if blood pressure is labile or if restoration of arterial pressure is labile or if restoration of arterial perfusion pressures is expected to be a perfusion pressures is expected to be a lengthy process.lengthy process.

Monitoring of Tissue PerfusionMonitoring of Tissue Perfusion

Signs of impaired organ perfusion that Signs of impaired organ perfusion that occur in shock include:occur in shock include:– Cool, vasoconstricted skinCool, vasoconstricted skin– Obtundation or restlessnessObtundation or restlessness– Oliguria/anuriaOliguria/anuria– Lactic AcidosisLactic Acidosis– Gastric intramucosal acidosisGastric intramucosal acidosis

Clinical findings of shock may be modified Clinical findings of shock may be modified by preexisting disease.by preexisting disease.

Restoration of Tissue PerfusionRestoration of Tissue Perfusion

Hypotension is sepsis results from:Hypotension is sepsis results from:– A loss of plasma volume into the interstitial A loss of plasma volume into the interstitial

space.space.– Decreases in vascular tone.Decreases in vascular tone.– Myocardial depression.Myocardial depression.

IV fluids, pRBC’s, and pressors are often IV fluids, pRBC’s, and pressors are often required, depending upon the patient’s required, depending upon the patient’s volume status, cardiac status, and the volume status, cardiac status, and the severity of shock.severity of shock.

Intravenous FluidsIntravenous Fluids

Rapid, large volume infusions of IVF are Rapid, large volume infusions of IVF are usually indicated as initial therapy in usually indicated as initial therapy in patients with septic shock.patients with septic shock.

Fluid therapy should be administered in Fluid therapy should be administered in well-defined, rapidly infused boluses.well-defined, rapidly infused boluses.– Careful monitoring is essential in this approach Careful monitoring is essential in this approach

because patients with sepsis can develop because patients with sepsis can develop pulmonary edema at wedge pressures <18pulmonary edema at wedge pressures <18

VasopressorsVasopressors

Second line agents in the treatment of severe Second line agents in the treatment of severe sepsis and septic shocksepsis and septic shock– IVF are preferred so long as they increase CO and/or IVF are preferred so long as they increase CO and/or

BP without seriously impairing gas exchange.BP without seriously impairing gas exchange.

Large trials comparing outcomes with different Large trials comparing outcomes with different vasopressors have not been performed, and vasopressors have not been performed, and therefore there is no definitive evidence of the therefore there is no definitive evidence of the superiority of one pressor over another.superiority of one pressor over another.

Identification of the Septic FocusIdentification of the Septic Focus

A careful history and physical may yield A careful history and physical may yield clues to the source of sepsis and help guide clues to the source of sepsis and help guide subsequent microbiologic evaluation.subsequent microbiologic evaluation.

Gram stain of suspicious fluids may give Gram stain of suspicious fluids may give early clues to the etiology of infection while early clues to the etiology of infection while cultures are incubating.cultures are incubating.

Eradication of InfectionEradication of Infection

Essential to the successful treatment of Essential to the successful treatment of septic shock.septic shock.

Source control should be undertaken when Source control should be undertaken when possible because undrained foci of infection possible because undrained foci of infection may not respond to antibiotics alone.may not respond to antibiotics alone.

An empiric regimen of broad spectrum An empiric regimen of broad spectrum antibiotics should also be instituted as early antibiotics should also be instituted as early as possible after appropriate cultures have as possible after appropriate cultures have been collected.been collected.

Eradication of InfectionEradication of Infection

Choice of antibiotics should be based upon Choice of antibiotics should be based upon clinical and Gram stain data and local resistance clinical and Gram stain data and local resistance patterns, and then should be adjusted as culture patterns, and then should be adjusted as culture results become available.results become available.

Potential gram negative pathogens are generally Potential gram negative pathogens are generally covered with two effective agents from different covered with two effective agents from different antibiotic classes.antibiotic classes.

Regardless of the antibiotic regimen, patients Regardless of the antibiotic regimen, patients should be observed closely for toxicity, evidence should be observed closely for toxicity, evidence of response, and for the development of of response, and for the development of superinfection.superinfection.

Recombinant Human Activated Recombinant Human Activated Protein C (Xigris)Protein C (Xigris)

Dose 24 mcg/kg/hr for 96 hoursDose 24 mcg/kg/hr for 96 hours 28 day mortality rate was significantly lower.28 day mortality rate was significantly lower. Increased incidence of serious bleeding, including Increased incidence of serious bleeding, including

fatal intracranial hemorrhage.fatal intracranial hemorrhage. Treatment was of greater benefit in the most acutely Treatment was of greater benefit in the most acutely

ill patients.ill patients. Analysis of secondary end points suggested that the Analysis of secondary end points suggested that the

incidence of MOD was lower in patients treated incidence of MOD was lower in patients treated with Xigris, and that therapy was associated with with Xigris, and that therapy was associated with more rapid recovery of cardiac and pulmonary more rapid recovery of cardiac and pulmonary function.function.

Inclusion CriteriaInclusion Criteria

                                                                       

                                                                                                                                                                 

Exclusion CriteriaExclusion Criteria

PregnancyPregnancy Age < 18Age < 18 Weight > 135kgWeight > 135kg Platelet < 30,000Platelet < 30,000 Known Known

hypercoagulable hypercoagulable conditionsconditions

HIV with CD4<50HIV with CD4<50

CKD requiring HDCKD requiring HD Conditions that Conditions that

increase the risk of increase the risk of bleedingbleeding

Portal hypertensionPortal hypertension H/O bone marrow, H/O bone marrow,

lung, liver transplant.lung, liver transplant. Acute pancreatitisAcute pancreatitis

CorticosteroidsCorticosteroids

Many patients with septic shock have a Many patients with septic shock have a relative adrenal insufficiency.relative adrenal insufficiency.

Physiologic stress dose steroids were Physiologic stress dose steroids were associated with a shorter duration of pressor associated with a shorter duration of pressor dependence, as well as an improvement in dependence, as well as an improvement in 28-day mortality.28-day mortality.

Therapy was not associated with an Therapy was not associated with an increased incidence of adverse events.increased incidence of adverse events.

Monitor for hyperglycemia in this setting.Monitor for hyperglycemia in this setting.

NutritionNutrition

Adequate nutritional support is essential for Adequate nutritional support is essential for optimal immune function, and appears beneficial optimal immune function, and appears beneficial in both the prevention and the treatment of sepsis.in both the prevention and the treatment of sepsis.– Improves wound healing and decreases susceptibility to Improves wound healing and decreases susceptibility to

infection.infection.– Enteral nutrition may offer more benefit than parenteral Enteral nutrition may offer more benefit than parenteral

nutrition.nutrition.– Nutritional support results in higher lymphocyte counts Nutritional support results in higher lymphocyte counts

and higher serum albumin levels.and higher serum albumin levels.– Hyperglycemia and insulin resistance are common in Hyperglycemia and insulin resistance are common in

critically ill patients. Evidence suggests that aggressive critically ill patients. Evidence suggests that aggressive glucose control may improve outcome in these patients.glucose control may improve outcome in these patients.

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