Circulatory failure may be due to failure of the myocardium, inadequate preload (ventricular filling) or pooling of blood for example in venous reservoirs which does not reach the heart. After ensuring that there is an adequate preload with infusions if necessary and hemodynamic monitoring, inotropic agents may be necessary to improve cardiac contractility.
Inotropes
The aim two to improve cardiac contractility. Ideally there should not be undue tachycardia,propensity for cardiac arrhythmias or a significant increase in myocardial oxygen consumption,interaction with other drugs or effect on other organs. The volume status, vasomotor tone whether vasoconstricted or vasodilated and cardiac state should be carefully assessed. An acute inotropic response in the physiological state is a rapid increase in tissue levels of cyclic AMP. The same principle is involved in the use of exogenous catecholamines which stimulate the beta adrenergic receptors and raise cyclic AMP or less commonly when the breakdown of cyclic AMP is inhibited by phosphodiesterase (PDE) inhibitors like Milrinone.
Receptors
There are 2 main types of adrenergic receptors. All catecholamines act directly on the adrenergic receptors. Beta receptor stimulation results in increased ATP conversion to cyclic AMP. Alpha 1 receptor activation acts independently of cyclic AMP and results in release of calcium and increased membrane permeability to calcium.
Norepinephrine is the agonist which acts on Beta receptors. There is depletion of norepinephrine stores in heart failure and a down regulation in the number of Beta receptors. Therefore, Alpha 1 and Alpha 2 receptors are important in maintaining the contractility in the failing myocardium.Epinephrine, Norepinephrine and Dopamine are all naturally occurring compounds. All three are Beta agonists at low doses with increasing Alpha1 receptor activity at higher doses. All increase stroke volume, cardiac output and mean arterial pressure without much change in the heart rate and little by way of arrhythmias. Dopamine is the precursor of Noradrenaline which in turn is the precursor of adrenaline.
Inotropes
The aim two to improve cardiac contractility. Ideally there should not be undue tachycardia,propensity for cardiac arrhythmias or a significant increase in myocardial oxygen consumption,interaction with other drugs or effect on other organs. The volume status, vasomotor tone whether vasoconstricted or vasodilated and cardiac state should be carefully assessed. An acute inotropic response in the physiological state is a rapid increase in tissue levels of cyclic AMP. The same principle is involved in the use of exogenous catecholamines which stimulate the beta adrenergic receptors and raise cyclic AMP or less commonly when the breakdown of cyclic AMP is inhibited by phosphodiesterase (PDE) inhibitors like Milrinone.
Receptors
There are 2 main types of adrenergic receptors. All catecholamines act directly on the adrenergic receptors. Beta receptor stimulation results in increased ATP conversion to cyclic AMP. Alpha 1 receptor activation acts independently of cyclic AMP and results in release of calcium and increased membrane permeability to calcium.
Norepinephrine is the agonist which acts on Beta receptors. There is depletion of norepinephrine stores in heart failure and a down regulation in the number of Beta receptors. Therefore, Alpha 1 and Alpha 2 receptors are important in maintaining the contractility in the failing myocardium.Epinephrine, Norepinephrine and Dopamine are all naturally occurring compounds. All three are Beta agonists at low doses with increasing Alpha1 receptor activity at higher doses. All increase stroke volume, cardiac output and mean arterial pressure without much change in the heart rate and little by way of arrhythmias. Dopamine is the precursor of Noradrenaline which in turn is the precursor of adrenaline.
Beta Adrenergic Agonists
These drugs cause their positive inotropic effect by activating α-receptors with subsequent stimulation of adenylate cyclase and increased cAMP.
Dopamine
Dopamine is an endogenous catecholamine precursor with selective â1 activity. However, it also stimulates the release of norepinephrine. At low doses, it stimulates renal dopaminergic receptors,which causes increased renal blood flow and diuresis. This effect has been increasingly questioned. Dopamine is not effectively absorbed orally. It is rapidly metabolized by the body and has a half-life of < 2 min. It is administered IV, by continuous infusion (1-20 μg/kg/min).
Cardiac arrhythmias may occur due to â-adrenergic activity. Indications include cardiogenic or endotoxic shock and oliguria. In patients with advanced HF, who often have depleted intracardiac norepinephrine stores, dopamine is a less effective positive inotropic drug than other “directly” acting inotropes. At higher infusion rates (5 to 20 ìg/kg/min), peripheral vasoconstriction occurs as a result of direct alpha-adrenergic receptor stimulation. Increases in systemic vascular resistance are common even at intermediate infusion rates. On initial administration, tachycardia and arrhythmia tend to be more pronounced than with dobutamine and are related to cardiac norepinephrine release.
The limitations of dobutamine are that it (1) is a relatively weak beta-agonist, (2) only modestly lowers elevated pulmonary artery pressure, (3)eventually produces desensitization phenomena when used chronically, and (4) cannot be effectively used in the presence of high levels of beta-adrenergic receptor blockade. The first three of these limitations can be overcome by combining Dobutamine with a Phosphodiesterase Inhibitor which results in additive effects on myocardial performance, substantial reductions in pulmonary wedge and pulmonary artery pressure.
E p i n e p h r i n e ( A d r e n a l i n e )
Epinephrine compared with other inotropic drugs, causes the greatest increase in the rate of energy usage and myocardial oxygen demand. This increase in oxygen need may be detrimental to the failing heart. Epinephrine also causes vasoconstriction and bronchodilation. Epinephrine cannot be given orally. Absorption is more rapid after IM versus SC administration. Epinephrine is available in several preparations and is effective after IV, pulmonary, and nasal administration.However, because of the decreased efficiency of cardiac work, epinephrine is not generally used as a positive inotrope. Epinephrine is an excellent positive inotropic agent in the denervated,transplanted heart because neuronal reuptake is no longer a factor. The dose of epinephrine usually ranges from 0.05 to 0.50 ìg/kg/min. It is used in emergency therapy of cardiac arrest and anaphylactic shock. Ventricular arrhythmias can be expected.
Norepinephrine (Noradrenaline)
Norepinephrine is a mild (10 to 30 fold) β1 vs. β2 receptor–selective agonist with relatively high affinity for alpha1 receptors. This constellation of properties means that norepinephrine will be a powerful vasoconstrictor, but not a very powerful inotrope in hearts. Norepinephrine does not have any recommended uses in subjects with cardiac decompensation.Those who need peripheral vascular resistance support (such as in sepsis, iatrogenic overvasodilation, or brain injury) are served better by dopamine or dopamine plus phenylephrine administration.
Isoproterenol
Isoproterenol is a synthetic catecholamine. It is predominantly a chronotrope. Increases heart rate and cardiac output without any significant change in the blood pressure. Disproportinate increase in myocardial oxygen consumption. The BP may fall because of predominant Beta 2 receptor induced vasodilation. Tachycardia and the potential for other arrhythmias excludes its use in the cardiac patient. It is used for therapy of bradyarrhythmias or AV block. As a therapeutic inotrope,isoproterenol has only one indication—postoperatively after heart transplantation. Isoproterenol isuseful in this setting because an increase in heart rate is not a problem in the presence of normal coronary arteries, and the chronotropic stimulation is useful in the newly transplanted heart,which often has a sluggish sinus node mechanism. The pulmonary vasodilator properties of isoproterenol are also useful in this setting, where pulmonary artery pressure and pulmonary vascular resistance are usually elevated. The dose of isoproterenol ranges from 0.005 to 0.05 mcg/kg/min.
Phenylnephrine
This is a pure alpha-agonist with no beta-agonist activity. Even though alpha1 receptors can mediate a small inotropic response in the human heart, phenylephrine should be used only to increase systemic vascular resistance in settings in which dopamine is not effective. The usual dose of phenylephrine ranges from 0.3 to 3 μg/kg/min.
Calcium
Calcium is also a positive inotrope but must be given as a slow IV injection or infusion. Calcium must be administered carefully because it can cause cardiac rigor and standstill at high doses. The gluconate form is preferred to calcium chloride. In general should be used only if there is significant hyperkalemia, hypocalcemia or poisoning from calcium channel blockers. When cardiogenic shock is profound, calcium is often added to an epinephrine infusion to produce synergistic increases in contractility and an increase in vascular tone. This combination, made by adding 1 gm of CaCl2 to 250 ml of intravenous solution containing epinephrine and called “Epi-Cal,” has never been subjected to a clinical trial and should be used in resuscitative settings only.
Phosphodiesterase Inhibitors
Milrinone is a Phosphodiesterase inhibitor (PDE) which increases levels of cyclic AMP. The cardiac effects are increased inotropy and improved diastolic relaxation (lusitropy). Also cause potent vasodilation with decrease in pre and afterload. This combined effect has been termed inodilation. Enoximone has less vasodilation. Combined use with catecholamines like Epinephrine and Norepinephrine may be necessary. No significant increase in heart rate or myocardial oxygen consumption. Milrinone: Loading 50 mcg/kg and maintenance of 0.5 mcg/kg/min.
Doses
All used intravenously (IV).
Steady state reached in 5-10 minutes.
Adrenaline, Noradrenaline and Isoprenaline all have side chains which is associated with 100 times greater potency than dopamine or dobutamine.
All catecholamines have very short half lives. Mainly due to reuptake by the tissues and degradation in liver and lung.
Epinephrine (Adrenaline): 1-70 mcg/min.
For CPR given as bolus of 1mg and infusion of 10-100 mcg/kg/min.
In aystole an IV dose of 5 mg has been used.
For anaphylaxis a dose of 0.3-1.0 mg(often 0.5 mg) given SC or IM.
Norepinephrine: 1-70 mcg/min.Dobutamine:
2 - 2 0 m c g / k g / m i n ( 1 0 0 -2 0 0 0 m c g / m i n ) .
Dobutamine infusions are initiated at 2 to 3 mcg/kg/min and are titrated upward according to the patient’s hemodynamic response (usually not higher than 20 mcg/kg/min).
D o p a m i n e : 1 - 2 0 m c g / k g / m i n ( 1 0 0 - 2 0 0 0 m c g / m i n ) .
Isoproterenol: Range 0.005 to 0.05 mcg /kg/min.
Phenylephrine: Range from 0.3 to 3 mcg/kg/min.
Milrinone : Loading 50 and maintenance 0.5 m c g / k g / m i n .
These drugs cause their positive inotropic effect by activating α-receptors with subsequent stimulation of adenylate cyclase and increased cAMP.
Dopamine
Dopamine is an endogenous catecholamine precursor with selective â1 activity. However, it also stimulates the release of norepinephrine. At low doses, it stimulates renal dopaminergic receptors,which causes increased renal blood flow and diuresis. This effect has been increasingly questioned. Dopamine is not effectively absorbed orally. It is rapidly metabolized by the body and has a half-life of < 2 min. It is administered IV, by continuous infusion (1-20 μg/kg/min).
Cardiac arrhythmias may occur due to â-adrenergic activity. Indications include cardiogenic or endotoxic shock and oliguria. In patients with advanced HF, who often have depleted intracardiac norepinephrine stores, dopamine is a less effective positive inotropic drug than other “directly” acting inotropes. At higher infusion rates (5 to 20 ìg/kg/min), peripheral vasoconstriction occurs as a result of direct alpha-adrenergic receptor stimulation. Increases in systemic vascular resistance are common even at intermediate infusion rates. On initial administration, tachycardia and arrhythmia tend to be more pronounced than with dobutamine and are related to cardiac norepinephrine release.
The limitations of dobutamine are that it (1) is a relatively weak beta-agonist, (2) only modestly lowers elevated pulmonary artery pressure, (3)eventually produces desensitization phenomena when used chronically, and (4) cannot be effectively used in the presence of high levels of beta-adrenergic receptor blockade. The first three of these limitations can be overcome by combining Dobutamine with a Phosphodiesterase Inhibitor which results in additive effects on myocardial performance, substantial reductions in pulmonary wedge and pulmonary artery pressure.
E p i n e p h r i n e ( A d r e n a l i n e )
Epinephrine compared with other inotropic drugs, causes the greatest increase in the rate of energy usage and myocardial oxygen demand. This increase in oxygen need may be detrimental to the failing heart. Epinephrine also causes vasoconstriction and bronchodilation. Epinephrine cannot be given orally. Absorption is more rapid after IM versus SC administration. Epinephrine is available in several preparations and is effective after IV, pulmonary, and nasal administration.However, because of the decreased efficiency of cardiac work, epinephrine is not generally used as a positive inotrope. Epinephrine is an excellent positive inotropic agent in the denervated,transplanted heart because neuronal reuptake is no longer a factor. The dose of epinephrine usually ranges from 0.05 to 0.50 ìg/kg/min. It is used in emergency therapy of cardiac arrest and anaphylactic shock. Ventricular arrhythmias can be expected.
Norepinephrine (Noradrenaline)
Norepinephrine is a mild (10 to 30 fold) β1 vs. β2 receptor–selective agonist with relatively high affinity for alpha1 receptors. This constellation of properties means that norepinephrine will be a powerful vasoconstrictor, but not a very powerful inotrope in hearts. Norepinephrine does not have any recommended uses in subjects with cardiac decompensation.Those who need peripheral vascular resistance support (such as in sepsis, iatrogenic overvasodilation, or brain injury) are served better by dopamine or dopamine plus phenylephrine administration.
Isoproterenol
Isoproterenol is a synthetic catecholamine. It is predominantly a chronotrope. Increases heart rate and cardiac output without any significant change in the blood pressure. Disproportinate increase in myocardial oxygen consumption. The BP may fall because of predominant Beta 2 receptor induced vasodilation. Tachycardia and the potential for other arrhythmias excludes its use in the cardiac patient. It is used for therapy of bradyarrhythmias or AV block. As a therapeutic inotrope,isoproterenol has only one indication—postoperatively after heart transplantation. Isoproterenol isuseful in this setting because an increase in heart rate is not a problem in the presence of normal coronary arteries, and the chronotropic stimulation is useful in the newly transplanted heart,which often has a sluggish sinus node mechanism. The pulmonary vasodilator properties of isoproterenol are also useful in this setting, where pulmonary artery pressure and pulmonary vascular resistance are usually elevated. The dose of isoproterenol ranges from 0.005 to 0.05 mcg/kg/min.
Phenylnephrine
This is a pure alpha-agonist with no beta-agonist activity. Even though alpha1 receptors can mediate a small inotropic response in the human heart, phenylephrine should be used only to increase systemic vascular resistance in settings in which dopamine is not effective. The usual dose of phenylephrine ranges from 0.3 to 3 μg/kg/min.
Calcium
Calcium is also a positive inotrope but must be given as a slow IV injection or infusion. Calcium must be administered carefully because it can cause cardiac rigor and standstill at high doses. The gluconate form is preferred to calcium chloride. In general should be used only if there is significant hyperkalemia, hypocalcemia or poisoning from calcium channel blockers. When cardiogenic shock is profound, calcium is often added to an epinephrine infusion to produce synergistic increases in contractility and an increase in vascular tone. This combination, made by adding 1 gm of CaCl2 to 250 ml of intravenous solution containing epinephrine and called “Epi-Cal,” has never been subjected to a clinical trial and should be used in resuscitative settings only.
Phosphodiesterase Inhibitors
Milrinone is a Phosphodiesterase inhibitor (PDE) which increases levels of cyclic AMP. The cardiac effects are increased inotropy and improved diastolic relaxation (lusitropy). Also cause potent vasodilation with decrease in pre and afterload. This combined effect has been termed inodilation. Enoximone has less vasodilation. Combined use with catecholamines like Epinephrine and Norepinephrine may be necessary. No significant increase in heart rate or myocardial oxygen consumption. Milrinone: Loading 50 mcg/kg and maintenance of 0.5 mcg/kg/min.
Doses
All used intravenously (IV).
Steady state reached in 5-10 minutes.
Adrenaline, Noradrenaline and Isoprenaline all have side chains which is associated with 100 times greater potency than dopamine or dobutamine.
All catecholamines have very short half lives. Mainly due to reuptake by the tissues and degradation in liver and lung.
Epinephrine (Adrenaline): 1-70 mcg/min.
For CPR given as bolus of 1mg and infusion of 10-100 mcg/kg/min.
In aystole an IV dose of 5 mg has been used.
For anaphylaxis a dose of 0.3-1.0 mg(often 0.5 mg) given SC or IM.
Norepinephrine: 1-70 mcg/min.Dobutamine:
2 - 2 0 m c g / k g / m i n ( 1 0 0 -2 0 0 0 m c g / m i n ) .
Dobutamine infusions are initiated at 2 to 3 mcg/kg/min and are titrated upward according to the patient’s hemodynamic response (usually not higher than 20 mcg/kg/min).
D o p a m i n e : 1 - 2 0 m c g / k g / m i n ( 1 0 0 - 2 0 0 0 m c g / m i n ) .
Isoproterenol: Range 0.005 to 0.05 mcg /kg/min.
Phenylephrine: Range from 0.3 to 3 mcg/kg/min.
Milrinone : Loading 50 and maintenance 0.5 m c g / k g / m i n .
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