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Inotropic Therapy
Rationale for Using Inotropic Therapy inthe Critically Ill
REVERSING IMPAIRED MYOCARDIAL CONTRACTILITY
ACHIEVING SUPRANORMAL LEVELS OF OXYGEN DELIVERY
HIGH-RISK SURGICAL PATIENTS
CRITICALLY ILL PATIENTS
inotropic therapy is generallyconsidered includes cardiogenic shock, acute heart failure, or acuteexacerbation of chronic heart failure
use of such therapy in these clinical conditions seems logical on a purelypathophysiologic basis, no demonstration of a beneficial impact onmorbidity and mortality can be found in the literature.
increased mortality rates when given on a long-termbasis to patients with chronic heart failure
the long-term use of inotropes may lead to deterioration of left ventricularfunction through acceleration of myocardial cell apoptosis
deterioration of left ventricularfunction through acceleration of myocardial cell apoptosis
agents have negative inotropic effects, such as b-blockers, is now well establishedwhen1. cardiogenic shock( myocardial infarction or
acute myocarditis bridge to coronary revascularization or recovery
2. Refractory chronic heart failure bridge to transplantation
Inotropic therapy
ACHIEVING SUPRANORMAL LEVELS OF O2 DELIVERY1-High-Risk Surgical Patients
use of supranormal hemodynamic valuesin high-risk patients undergoing surgery as therapeutic endpoints was associated with a reduction in mortalityfrom 33% to 4%.
protocol group, dobutamine and dopamine were given as inotropic drugs—even in the absence of evidence of reduced cardiac contractility—when volume resuscitation (and packedred blood cells if necessary) failed to achieve supranormal values ofmyocardial oxygen delivery (DO2)4 (DO2 > 600 mL/min/m2).
related to the increased DO2 or antiinflammatory effects of catecholamines.
Critically Ill Patients
a pathologic myocardial oxygen consumption/oxygen delivery (VO2/DO2) dependency, presumably due to impaired oxygen extraction capabilities, has been reported invarious categories of acute illnesses such as sepsis and acute respiratory distress syndrome
increased blood lactate, a marker of global tissuehypoxia and to be associated with a poor outcome
manipulation of hemodynamic variablestoward values higher than physiologic values did not demonstrateany benefit
attempt to achieve supranormal hemodynamic targets in thegeneral population of critically ill patients is no longer recommended.in the early phase of septic shock when bloodflow and DO2 are generally low FOR rapidly restore normal global blood flow deleterious consequences of systemic hypoperfusion
EFFECTSINOTROPIC
LUSITROPIC CHRONOTROPIC,
DROMOTROPIC
VASOPRESSORS
Β1 AGONIST/STIMULATION: CHRONITROPIC, INOTROPICΒ2 AGONIST/STIMULATION: VASODILATION, BRONCHODILATIONΑ: VASOCONSTRICTIOND: INCREASES RENAL BLOOD FLOW
Natural as well as synthetic catecholamines enhance the Ca2+ cytosolicamount, which is directly related to the force of contractiona faster decrease in Ca2+ cytosolic concentration aftercontraction and accounting for the lusitropic effect.
Pharmacologic Propertiesof Inotropic Agents
Need to understand how they work to use effectively
Adrenergic precipitation of arrhythmiasDrive the heart too fast resulting in decreased filling time and decreased stroke volumeVasoconstriction of splachnic circulation and coronary arteriesInotropes may make certain patients hypotensive
PHARMACOLOGIC PROPERTIES OF THE INOTROPICAGENTS USED IN CLINICAL PRACTICE
Epinephrine
potent stimulator of α, β1, and β2 receptorscardiac β1 stimulation, epinephrine increases HR and inotropism.
α-mediated venous constriction promoting venous return and cardiacpreload results in increase in cardiac output
Epinephrine also facilitates ventricular relaxation and enhanced coronary blood flow through the increase in myocardial VO2.
Norepinephrine
It is a potent α- and β1-adrenergic agonist,but it has little activity on β2 receptors
α-adrenergic effect tarterial and venous constriction
β1 positive inotropic effect and increase SV
heart rate is unchanged or reduced, and the cardiac output can be unchanged. baroreflex stimulation following vasoconstriction
Coronary blood flow is enhancedsecondary to enhanced cardiac metabolism andbecause of normalization of diastolic blood pressure when low.
Dopamine
-2-5 mcg/kg/min renal flow => D1 receptors
- 5-10 mcg/kg/min => Beta 1 enhances inotropism and increases heart rate increases systolic blood pressure without altering diastolic blood pressure, because stroke volume is enhanced and arterialvascular tone only slightly altered
- 10-20 mcg/kg/min => alpha, vasoconstriction
several types of receptors that are activated at different levels of dopamine concentration
Dobutamine
β1-adrenergic stimulationeffects on adrenergic receptors are complex but
Dobutamine exerts no intrinsic vascular effect, because the vasoconstriction induced by α1 stimulation is counteracted by the β2 vasodilating effect.
Dopexamine
β2 and dopaminergic receptor
induces vasodilation and inotropic effect with substantiallyincreased stroke volume
no effect on α-adrenergic receptors
Isoproterenolβ-adrenergic agonist
β2 vasodilating effect it induces a fall in diastolic and meanblood pressure
β1-adrenergic activation systolic blood pressure is increased
increase in heart rate leads to enhanced cardiac outputincrease in myocardial VO2 is not compensated by coronary blood flow enhancement, so isoproterenol infusion may lead to myocardial ischemia, especially if there is preexisting coronary artery disease
no longer used
Phosphodiesterase Inhibitors
Despite the major role of catecholamines in the management of criticallyill patients with inadequate cardiac output, problems such astachycardia, arrhythmias, increased myocardial VO2, excessive vasoconstriction, or loss of effectiveness with prolonged exposure toβ-agonists may occur
increasing intracellular cAMP concentration
Vasodilation AND left ventricular preload is reduced
inotropic effect and heart rate is increased and increase incardiac output. facilitate ventricular relaxation
Synergic since β-agonists exert their action by increasing theproduction of cAMP, phosphodiesterase inhibition could enhancetheir adrenergic effects.
milrinone and enoximone
Calcium Sensitizers
levosimendan
increase the sensitivity of troponin C for Ca hence the force and duration of the cardiomyocytes’ contraction
increase the activity of the ATPase of the myofibrils,increasing the contractile force
Cardiac Myosin Activators
DECREASE IN β-ADRENERGIC RESPONSE
Hemodynamic Effects of InotropicAgents in Critically Ill Patients
EFFECTS ON CARDIAC OUTPUT
EFFECTS ON ARTERIAL OXYGEN CONTENT
EFFECTS ON TISSUE OXYGEN UTILIZATION
EFFECTS ON CARDIAC OUTPUT
Dobutamine and Dopamine
Epinephrine and Norepinephrine
Dopexamine
Dobutamine and DopamineDobutamine and dopamine are the β-adrenergic agents most widelyused in critically illIn acute heart failure
dobutamine (2.5-10 μg/kg/min) increased CO BY increase in SV in a dose-response dopamine increased SV and CO at 4 μg/kg/min at higher doses. because of an increase in left ventricular afterloadpulmonary artery occlusion pressure decreased with
dobutamine. increased with dopamine.
increase in left ventricular preload only with dopamine.
Dopamine at median or high doses has been one of the first-line catecholamines when arterial pressure remains low despite adequate volume resuscitation as it can exert both an α-mediated increase in arterial tone and a β-mediated increaseHR SV CO INCREASEminimal effects ON SVR
difficulty to predict clinical hemodynamic effects
great heterogeneity in the response to dopamine among septic patients
an increase in cardiac output and a decrease in SVR with dobutamine were reported in septic patients
septic shock WE HAVE DECREASE SVR WE HAVE TO GIVE DOBOTAMINE + VASOPRESSOR AGENT
dobutamine is the decrease in cardiac filling pressures that could allow an additional volume infusion to improve further cardiac output when necessary.
dobutamine can exert a more favorable effect on cardiac contractility than dopamine. recommendation to give dobutamine rather than dopamine
emphasize the unpredictability of the effects ofβ-agonist agents in patients with sepsis.
the absence of positive cardiac response to dobutamine seems a marker of poor outcome in septic shock patients.
Epinephrine and Norepinephrine
these agents have β1-adrenergic properties and thus are ableto increase myocardial contractility, they are used as vasoconstrictiveagents in cases of severe hypotension
the effects of norepinephrine on cardiac output are highly variable among septic patients. By contrast, epinephrine appeared to be a potent inotropic agent in most studies in septic patients
Dopexamineinotropic, afterload-reducing, and renal-vasodilating effects which could be useful for the management of acute exacerbation of congestive heart failureincrease cardiac output in patients with heart failure without altering blood pressure
doses up to 4 μg/kg/min
In cases of human sepsis, dopexamine produced dose-dependent increases in stroke volume and heart rate but dose-dependent decreasein SVR
Under these conditions, dopexamine at dosesranging drom 1 to 4 μg/kg/min could still enhance cardiac outputwithout altering blood pressure.
when an inotropic agent increases cardiac output in critically ill patients, it generally increases DO2 to the same extent
EFFECTS ON ARTERIAL OXYGEN CONTENT
CO D02
EFFECTS ON TISSUE OXYGEN UTILIZATION
reducing oxygen deficit depends on its capacity to provide oxygen in the most hypoxic tissues
concern
redistribution of blood flow is a characteristic pattern of shock states, and, inotropic drugs may also have vasoactive properties that interact with blood flow distribution.
EFFECTS ON TISSUE OXYGEN UTILIZATION
1.Cardiogenic Shock
redistribution of flow is A mechanism to deviate blood flow from nonvital organs towards vital organs
Administration of drugs with vasoactive properties may interfere with vasoregulation of regional blood flow
need to monitor as far as possible perfusion and/or function of critical organs.
Septic Shockmaldistribution of flow
Cause 1.microthrombosis,
2. alteration vascular reactivity
even when systemic oxygen transport is greater than normal.
defective tissueutilization
Result of study
Second, dopamine may have deleterious effects on gut mucosal perfusion29 despite its potential vasodilating action through mesenteric D receptors
Third, epinephrine is the least desirable effects on the splanchnic vasculature
Fourth, dopexamine can exert a favorable effect on splanchnic perfusion
sepsis can modify the impact of endogenous catecholamines and adrenergic drugs on regional blood Flows.
absence of reduction of renal blood flow observed during norepinephrine
to increase MAP toward
normal valuesFirst, dobutamine is likely to exert a beneficial effect on the gut mucosal perfusion
Main Indications for Inotropic Therapy in Patients with Circulatory Failure
• ACUTE HEART FAILURE AND CARDIOGENIC SHOCK
• SEPTIC SHOCK
Indicated
1- improve symptoms and end-organ function in patients with low output syndrome
2-left ventricular systolic dysfunction
3- systolic blood pressure below 90 mm Hg despite adequate filling pressure.
Dopamine is classically recommended as the inotropic agent ofchoice in the presence of SEVERE HYPOTENSION.
dobutamine is considered first-line therapy in the presence of predominant pump failure and volume overload but normal or moderately reduced blood pressure.
dopamine dobutamine low doses has been considered a therapy of interest when dobutamine alone fails to restore an adequate MAP in cardiogenic shock.
dobutamine is associated with an increased risk of death in acute heart failure patients.
Phosphodiesterase inhibitor therapy in chronic heart failure
INDICATION
(1 )patients with advanced heart failure awaiting transplantation
(2 )patients with acute decompensation of chronic heart failure unable to achieve stabilization with standard treatment
(3)patients with long-term b-blocker use, in whom short-term IV milrinone may even be preferred to dobutamine.
SEPTIC SHOCKIn cases of septic shock, dobutamine is generally considered the inotropicdrug of choice when myocardial contractility is severely depressed.
FIRST CHOICE DOBOTAMINE
Detection a vasodilatory effect, its use requires concomitant use of a vasopressor such as norepinephrine.
DOBOTAMINE +Norepinephrine. SEPTIC SHOCK
Epinephrine alternative dobutamine + norepinephrine.
Epinephrine is not recommended as the first-choice drug when treatmentof impaired cardiac contractility is considered
no longer responds to dobutamine administration Levosimendan alternative to dobutamine in case of severe septic myocardial.