Vasoactive drugs have two functions: (1) to improve cardiac perfusion pressure during cardiac arrest and (2) to support the circulation during hemodynamic compromise. During cardiac arrest, the myocardium needs to be perfused with adequately oxygenated blood before the return of spontaneous circulation can occur. Since a-adrenergic stimulation is responsible for improved coronary perfusion pressure, for this reason as well as others, adrenergic agents are used. Epinephrine is the agent most frequently employed. Currently, no evidence exists to support the superiority of an alternative agent although many have been tested in animal models.
Adrenergic agents are divided into pure a agents (phenylephrine), mixed a and b agents (epinephrine, norepinephrine, dopamine), and pure b or primarily b agonists (isoproterenol, dobutamine). The a receptors are found primarily in blood vessels, where a stimulation causes vasoconstriction. The b agonists work primarily on the heart and promote increased heart rate, increased contractility, and increased myocardial oxygen consumption. The b 2 receptors are found in smooth muscle of the bronchi, blood vessels, and uterus; stimulation causes bronchodilatation, vasodilatation, and uterine relaxation. If the etiology of the hemodynamic compromise is identified (e.g., cardiogenic, vasogenic, hypovolemic, or septic shock, etc.), then the judicious selection of a sympathomimetic agent can be achieved. See Table. .2.5.-3., T§ble,„„25-4,, and Iable.25:5 for details.
TABLE 25-3 Cardiovascular Actions and Signal Transduction Pathways Initiated by Adrenergic Receptor Activation
TABLE 25-4 Ability of Commonly Used Sympathomimetic Agents to Stimulate Adrenergic Receptors
EPINEPHRINE Actions Epinephrine is a potent, nonselective a- and b-adrenergic agonist. It is first-line therapy for cardiac arrest. The myocardium needs to be perfused before return of spontaneous circulation can occur. The a-adrenergic properties of epinephrine increase coronary artery perfusion pressure, which improves myocardial blood flow. Epinephrine is also a potent vasoconstrictor and increases mean arterial pressure by stimulating a-adrenergic receptors. This effect causes vasoconstriction of arterioles in the skin, mucosa, and mesenteric vasculature, redistributing blood to the heart and brain, and in turn results in improved cardiac and cerebral perfusion during resuscitation. However, its b-adrenergic qualities can have deleterious effects in the patient with myocardial ischemic or coronary artery disease. The b agonists increase heart rate, improve myocardial contractility, and therefore increase myocardial oxygen demand.
The b2 adrenergic effects of epinephrine cause bronchodilation and antagonize the effects of histamine. Therefore, epinephrine is a useful adjunct for the treatment of severe bronchospasm and severe hypersensitivity reaction.
Pharmacokinetics Both the onset and the duration of action of epinephrine are relatively short: 1 to 2 min and 2 to 10 min, respectively. The drug quickly becomes fixed in the tissues and is rapidly inactivated via oxidation by monoamine oxidase (MAO) and via methylation by catechol-O-methyltransferase (COMT). Subsequent metabolites are excreted in the urine as sulfates and glucuronides.
Common ED Indications Epinephrine is considered a first-line agent in the treatment of cardiac arrest and may be used in pulseless VT/VF that has not responded to electrical countershock, asystole, and pulseless electrical activity (PEA). The drug has also been purported to "coarsen" fine ventricular fibrillation, but there is no documented evidence that this is true. Epinephrine does, however, increase the likelihood of continued hemodynamic stability in animals that have been successfully defibrillated. This has been attributed to the effect of epinephrine on systemic vascular resistance. Historically, the standard 1-mg dose came from the operating room practice of intracardiac injections, which were effective in restarting the arrested heart. But when studies showed that 1 to 3 mg of intracardiac epinephrine seemed to be more effective, higher dosages were adopted. Further animal studies were performed, and their dose-response curves demonstrated that vasoactive effects of epinephrine were dose-dependent. The lower doses favored b-adrenergic effects (cardiac stimulation), while higher doses revealed a-agonist effects (vasoconstriction). Over the years, it was assumed that 1 mg of epinephrine administered intravenously was equivalent and would be useful for all body weights. The dose-response curve was studied in the 1980s and early 1990s, revealing that higher doses of epinephrine (ranging from 0.045 to 0.2 mg/kg) were required to improve hemodynamics and demonstrate increased rates of return of spontaneous circulation (ROSC). However, trials failed to demonstrate significant improvement in survival rates to hospital discharge compared with the standard epinephrine doses (see "Dosing and Administration," below). Experience with "high-dose" epinephrine resulted in increased numbers of patients with ROSC admitted to intensive care settings, who previously would likely have failed resuscitation. While these results were initially exciting, the routine practice of administering high-dose epinephrine has waned as clinicians have come to appreciate the poor outcomes and needless consumption of precious medical resources.
Epinephrine is also used as an antidote to reverse bronchospasm due to anaphylactic and hypersensitivity reactions. It can be used as a vasopressor to increase blood pressure in septic shock. It should be employed as second-line therapy after norepinephrine. Be aware of its b-agonist properties, namely cardiac stimulation, which can increase the risk of dysrhythmias.
Dosing and Administration Current AHA guidelines recommend that epinephrine in a 1-mg (1:10,000) IV bolus continue to be the initial dose in cardiac arrest. It is now recommended that the dosing frequency be increased to 3 to 5 min from a 5-min interval. The AHA recognizes that higher doses of epinephrine are acceptable but can neither recommend nor discourage their use; however, they do say higher doses should be used only after the 1-mg dose has failed. The intermediate epinephrine dose suggestion is 2 to 5 mg IV push, also given every 3 to 5 min; the escalating regimen is 1 mg to 3 mg to 5 mg IV push, 3 min apart; the high dose reflects use of a bolus of 0.1 mg/kg every 3 to 5 min.
Epinephrine may be given by peripheral vein, central line, or endotracheally. The optimal dose for endotracheal drug delivery is unknown; however, a dose that is at 1
least 2 to 22 times the peripheral intravenous dose may be needed. Endotracheal (ET) administration is performed by placing 10 mL of a 1:10,000 solution (preload syringe) down the ET tube and then performing several rapid ventilations to disperse the drug throughout the airways for maximal absorption. If the more concentrated epinephrine vial is used (30 mg/30 mL, 1:1000), the dose should be diluted to 10 mL.
Intracardiac administration should be used only during open cardiac massage so as to avoid the risk of pneumothorax, coronary artery laceration, and cardiac tamponade. Transthoracic intracardiac injections will interrupt ventilations and closed chest compressions and are thus no longer recommended.
Although ephinephrine is not the first choice, a continuous epinephrine infusion can be used to elicit the vasopressor response in patients who are not in cardiac arrest. The initial dose should begin at 1 mg/min (range 2 to 10 mg/min) and be titrated to a desired hemodynamic response. Continuous intravenous infusions of epinephrine should be administered by central venous access to ensure prompt transport to the heart and reduce the risk of extravasation.
Adverse-Effects Profile Adverse effects are of minimal importance in the setting of cardiac arrest. Epinephrine does increase myocardial oxygen consumption significantly and thus can exacerbate ventricular irritability in the setting of myocardial ischemia. The a-adrenergic activity of epinephrine produces an increase in systemic vascular resistance, which could conceivably be detrimental to a failing myocardium in that increased afterload can significantly decrease cardiac output. Also, if the patient is resuscitated, hypertension, tachycardia, and dysrhythmias should be anticipated. Because epinephrine causes renal artery vasoconstriction, it may cause a detrimental decrease in the glomerular filtration rate (GFR). Epinephrine is not compatible with alkaline solutions (e.g., sodium bicarbonate) in the same intravenous line, as some studies show slow inactivation of catecholamine.
DOPAMINE Actions Dopamine (Intropin), an endogenous catecholamine and the precursor of endogenous norepinephrine, acts on dopaminergic, b 1 and a receptors. In low doses (1 to 3 pg/kg per min), dopamine acts on dopaminergic receptors, causing vasodilation of the renal, mesenteric, coronary, and intracerebral vascular beds. This effect improves organ perfusion and increases urine output. At moderate doses (3 to 10 pg/kg per min), dopamine acts on its b -,-adrenergic receptors, exerting inotropic and chronotropic effects and increasing cardiac output without marked increases in pulmonary wedge pressure. Stimulation of a receptors increases peripheral resistance, increases pulmonary wedge pressure, and decreases blood flow to the kidney. The a effects begin at 10 pg/kg per min and predominate above 15 pg/kg per min.
Pharmacokinetics Dopamine has an onset of action within 2 to 4 min and a duration of action of less than 10 min. It is used only as an intravenous infusion. Renal response may take 20 to 30 min. Dopamine is metabolized primarily (75 percent) to homovanillic acid and other metabolites (including norepinephrine) by MAO and COMT and is subsequently excreted in the urine. Only a fraction of the dose eliminated by the kidneys is unchanged dopamine.
Common ED Indications Dopamine is used to treat hemodynamic compromise associated with MI, heart failure, septic shock, and renal failure. It is indicated for reversing hemodynamically significant hypotension due to MI, overt heart failure, renal failure, and chronic CHF when fluid resuscitation is unsuccessful (using the appropriate crystalloid or colloid solution) or not appropriate. It is also used to improve renal blood flow and to increase urine output, especially in the patient with septic shock. It is a preferred agent for treatment of cardiogenic shock.
Dopamine can be used in septic shock, especially if the primary goal is improvement in myocardial contractility. At high a-adrenergic doses (>10 pg/kg per min), dopamine can effectively raise the blood pressure in the fluid-resuscitated patient with septic shock. However, cardiac stimulation also occurs at high doses, which increases the risk of dysrhythmias. Often low-dose dopamine is used in combination with a more pure a vasoconstrictor to treat septic shock. Dopamine should be avoided in trauma until the patient has been adequately fluid-resuscitated.
Dosing and Administration The range for low-dose dopamine is 1 to 3 pg/kg per min, while the moderate dose is 3 to 10 pg/kg per min. High-dose dopamine begins at 10 pg/kg per min and should be titrated to adequate blood pressure response. These three levels of dosage are also referred to as "renal," "cardiac," and "vasopressor," respectively, in recognition of the different physiologic effects at different doses. Renal dose dopamine improves renal blood flow and urine output. Cardiac dose dopamine improves myocardial contractility and increases heart rate secondary to b -,-adrenergic effects. Peripheral arterial and venous vasoconstriction caused by a-adrenergic stimulation occurs with vasopressor dose dopamine. As with all vasoactive infusions, dopamine should be discontinued by tapering the dosage. Most patients can be managed on 20 pg/kg per min or less. If higher doses are needed for septic shock, an intravenous norepinephrine infusion should be added. The combination of dopamine and dobutamine improves cardiac performance during cardiogenic shock.
Adverse-Effects Profile Dopamine may produce dose-dependent adverse effects, including hypotension at low infusion rates, hypertension at high infusion rates, ectopic beats, headache, nausea, vomiting, angina pectoris, and tachycardia. Necrosis may occur if the infusion extravasates. Gangrene of the extremities has occurred in patients with occlusive vascular disease or diabetes as well as in those who received prolonged high-dose infusions. Monoamine oxidase inhibitors, halogen anesthetics, sympathomimetics, and phosphodiesterase inhibitors will prolong and intensify the effects of dopamine, possibly causing hypertensive and dysrhythmogenic activity. Phenytoin may interact with dopamine and cause hypotension, seizures, and bradycardia. Dopamine is contraindicated in pheochromocytoma. Like epinephrine, dopamine should not be mixed with alkaline solutions in the same line.
DOBUTAMINE Actions Dobutamine (Dobutrex) is a synthetic sympathomimetic agent that exerts potent inotropic and mild chronotropic activity by directly stimulating b-adrenergic receptors. Dobutamine also has mild aragonist activity, but the effects are balanced by the more potent b2-agonist effects, cumulatively resulting in mild vasodilation. Dobutamine has potent b 1 effects, which make it an excellent inotrope, but it lacks the a vasoconstricting activity of dopamine. Doses of 2 to 20 pg/kg per min increase cardiac output, induce peripheral vasodilation, and decrease pulmonary occlusive pressures, causing minimal increase in heart rate.
However, higher doses of dobutamine will accelerate the heart rate and induce dysrhythmogenic effects. An increased cardiac output usually results in increased renal and mesenteric blood flow.
Pharmacokinetics Dobutamine has an onset of action of 1 to 2 min, but peak plasma levels may not be reached for 10 min. Its duration of action is 10 to 15 min. The plasma half-life is 2 min. Dobutamine is metabolized in the liver and other tissues by COMT and glucuronic acid, and over two-thirds of a dose is excreted as metabolites in the urine within 48 h.
Common ED Indications Dobutamine is used to increase inotropic activity in the short-term management of cardiac decompensation due to depressed contractility resulting either from organic heart disease or from cardiac surgical procedures. The drug should be used to increase cardiac output in patients with chronic CHF when standard therapy (diuretics, vasodilators, and digoxin) fails to improve symptoms and/or in the patient with pulmonary congestion and low cardiac output.
Dosing and Administration Dobutamine is administered only by intravenous infusion. The dosage range is 2 to 20 pg/kg per min; however, most patients can be maintained on 10 pg/kg per min or less. In some cases, very low doses (0.5 pg/kg per min) may be effective. Conversely, infusions up to 40 pg/kg per min have been used, but doses greater than 20 pg/kg per min should be used with caution because of increased risks of tachydysrhythmias. To assess the effectiveness of the drug correctly, patients should be monitored with a Swan-Ganz catheter.
Adverse-Effects Profile The primary adverse effects of dobutamine are increased heart rate (increases greater than 5 to 15 beats per minute are uncommon), blood pressure (increases greater than 10 to 20 mmHg are uncommon), and ectopic dysrhythmias (escape beats, unifocal and multifocal ventricular ectopic beats, and ventricular bigeminy). Less common effects include headache, paresthesias, tremors, nausea, angina, and dyspnea. Increases in heart rate greater than 10 percent may induce or exacerbate myocardial ischemia.
NOREPINEPHRINE Actions Norepinephrine bitartrate (Levophed) is identical to the endogenous catecholamine synthesized in the adrenal medulla and sympathetic nervous tissue. Norepinephrine acts primarily on a receptors, inducing powerful vasoconstrictor actions on arterial and venous beds (i.e., renal and mesenteric vasoconstriction). It is particularly useful in patients with dopamine refractory septic shock. The drug also has direct action on b 1 receptors, thus inducing inotropic and chronotropic effects. Paradoxical decreases in heart rate may result from reflex increases in parasympathetic tone. Norepinephrine therefore produces less tachycardia than dopamine. It differs from epinephrine in that it has little effect on b 2 receptors.
Pharmacokinetics Norepinephrine is administered only as intravenous infusion. The pressor effect has an onset of action within 1 to 3 min and stops within 5 to 10 min of discontinuation of the infusion. The primary elimination of norepinephrine is via uptake by adrenergic neurons and metabolism in the liver and other tissues, mainly by COMT and to a lesser extent by MAO. Norepinephrine metabolites are excreted in the urine as sulfate and glucuronate conjugates.
Common ED Indications Norepinephrine is used primarily as a vasopressor for the treatment of severe hypotension refractory to fluids and other pressor agents, specifically dopamine. Norepinephrine may be particularly effective when endogenous norepinephrine stores are low. This scenario may arise in patients who have been on prolonged infusions of dopamine. To a certain degree, norepinephrine increases inotropic activity and may be indicated in severe hypotension occurring during an AMI. However, norepinephrine is a potent vasoconstrictor that increases afterload and may impede cardiac output. Therefore norepinephrine should be employed in cardiogenic shock only after more traditional therapy has failed. Other specific uses for norepinephrine include controlling hypotensive states during poliomyelitis, treating drug overdose (various phenothiazines and tricyclic antidepressants), and for spinal anesthesia, pheochromocytomectomy, and sympathectomy. Its potent a effects make it a good choice to treat septic shock.
Dosing and Administration Norepinephrine should be used only as an intravenous infusion. The initial adult dose is 0.5 to 1 pg/min. Rates must be titrated carefully, increasing by 1 to 2 pg/min q3-5 min until a systolic blood pressure of 80 to 100 mmHg is attained. The drug should be infused at the lowest effective dose for the shortest period of time possible. Occasionally, high doses of norepinephrine may be necessary to reverse hypotension (e.g., 8 to 30 mg/min). Usually, the maintenance dose is 2 to 4 pg/min. Adjust the rate of flow q3-5 min to maintain blood pressure. Once the blood pressure is adequate, the infusion may be gradually titrated down. Abrupt withdrawal may result in acute hypotension.
Adverse-Effects Profile Large doses of norepinephrine may result in ventricular irritability, cardiac depression, decreased renal blood flow, and a reflex bradycardia. Acute hypertension may result in patients on MAO inhibitors or tricyclic antidepressants. Use norepinephrine with extreme caution in these patients. Use as large a vein as possible to minimize the risk of extravasation. If extravasation occurs, phentolamine, 5 to 10 mg in 10 to 15 mL of normal saline solution, should be infiltrated as soon as possible to prevent necrosis and sloughing. Check frequently for intravenous extravasation if a small vein is used. Norepinephrine is contraindicated in patients with hypotension resulting from cyclopropane or halogenated hydrocarbon anesthesia or uncorrected blood volume deficits as well as in mesenteric or peripheral vascular thrombosis. Norepinephrine must be used with caution in patients with known or suspected pulmonary hypertension, since norepinephrine is a potent vasoconstrictor of the pulmonary vasculature.
PHENYLEPHRINE Actions Phenylephrine is an a-adrenergic agent that possesses few b-adrenergic effects. It is useful for the treatment of septic shock, particularly if further cardiac stimulation is to be avoided. However, phenylephrine lacks the vasoconstrictor potency of epinephrine and norepinephrine.
Pharmacokinetics The vasoconstrictor activity of phenylephrine lasts approximately 20 min after intravenous infusion, 1 to 2 h after an intramuscular dose, and 50 min after subcutaneous administration. It is associated with reflex bradycardia, which is blocked by atropine. The sympathomimetic effects are potentiated by MAO inhibitors.
Common ED Indications Phenylephrine is a powerful a-receptor stimulant. It causes peripheral vasoconstriction, which causes an elevation of the systolic and diastolic blood pressure and reflex bradycardia. Unlike epinephrine and norepinephrine, phenylephrine lacks cardiac stimulant b effects. Therefore cardiac complications are rarely seen. It is useful in shock states caused by sepsis and by some drug toxicities. Patients with cardiogenic shock and left ventricular dysfunction require more b-inotropic support. Phenylephrine should be avoided in this patient population.
Dosing and Administration Phenylephrine can be administered intravenously or as a continuous infusion. In shock, the initial dose is 100 to 180 pg/kg as an intravenous infusion. Once the blood pressure is stable, the infusion can be decreased to 40 to 60 pg/kg. An alternate regimen is 0.1 to 0.5 mg intravenously q15 min. Do not exceed an individual dose of 0.5 mg IV. This should elevate the blood pressure for at least 15 min. Clinical response to the continuous infusion occurs between 40 to 180 pg/min. Blood pressure should be monitored continuously for both routes and hypertension avoided.
Adverse-Effects Profile Phenylephrine is associated with headache and restlessness. Reflex bradycardia commonly occurs. Since phenylephrine is pure a stimulant, cardiac dysrhythmias are rare. The a receptors are located in large coronary arteries but not commonly found in the small coronary arteries. Vasoconstriction of the large coronary arteries is particularly dangerous in the elderly, in those with severe atherosclerosis, and in patients with a history of MI. Extravasation of the drug is associated with sloughing and tissue necrosis, often requiring surgical debridement. Phentolamine, an a-adrenergic blocking agent, may prevent necrosis. (Dilute 10 mg of phentolamine in normal saline solution to a volume of 15 mL. Infiltrate the "at risk" area.)
ISOPROTERENOL Actions Isoproterenol is a synthetic sympathomimetic with strong b., and b2-adrenergic-agonist properties; it increases the myocardial oxygen consumption. b actions increase the inotropic and chronotropic activity of cardiac muscle, resulting in increased cardiac output despite a reduction in the mean blood pressure. The drop in blood pressure can be attributed to the b 2-adrenergic relaxation of smooth muscle in the splanchnic vascular bed and alimentary tract, the lungs, and skeletal muscle, which causes peripheral vasodilation and venous pooling. Therefore, isoproterenol is not a vasopressor agent and should not be used in shock.
Pharmacokinetics After intravenous administration, isoproterenol has an onset of action within 1 to 5 min and a duration of action lasting 1 to 2 h. Some 50 percent of the drug is eliminated unchanged in the urine, while 25 to 35 percent is metabolized primarily to 3-O-methylisoproterenol (which has been reported to have weak b-adrenergic blocking activity) by COMT in the lung, liver, and other body tissues and then excreted unchanged or as a sulfate conjugate.
Common ED Indications Isoproterenol is now indicated only for refractory torsades de pointes and immediate temporary management of hemodynamically significant bradycardias in the denervated heart of patients at or and after heart transplantation. Isoproterenol is not considered the drug of choice for either of these conditions; it should be considered only as a temporary measure until pacemaker therapy is instituted. For hemodynamically unstable bradydysrhythmias transcutaneous pacing (TCP) is the definitive treatment, since it provides better control and is a safer mode of therapy. Other agents that should be considered before isoproterenol are intravenous fluid challenge, atropine, and a dopamine or epinephrine infusion. The vasodilator effects of isoproterenol have been shown to lower coronary perfusion pressure during cardiac arrest and to increase the mortality rate in experimental animals; the drug has not been shown to be efficacious in cardiac arrest or for use in hypotension.
Dosing and Administration Isoproterenol should be administered only via intravenous infusion. The initial infusion rate, 2 to 10 Mg/min, should be titrated to the desired heart rate. The drug has been shown to be more helpful at low doses rather than high doses.
Adverse-Effects Profile It must be emphasized that the b1-agonist action of isoproterenol will cause an increase in chronotropic effect. This effect raises myocardial oxygen requirements and can possibly precipitate or exacerbate myocardial ischemia, inducing serious dysrhythmias (e.g., VT and VF). Other adverse effects include anxiety, mild tremors, and anginal pain in patients with previously reported angina pectoris. Therefore, the drug should be avoided in patients with preexisting ischemic heart disease. Isoproterenol may also induce tachydysrhythmias in hypokalemic and digoxin-toxic patients. The primary adverse effects from b 2-adrenergic actions are facial flushing, headache, and hypotension.
AMRINONE Actions Amrinone is thought to be a positive inotropic agent not related to digitalis glycosides, catecholamines (e.g., epinephrine, dopamine, and norepinephrine), or synthetic b1-adrenergic agonists (e.g., dobutamine and isoproterenol); it possesses potent vasodilator activity. While its true mechanism is not known, amrinone is believed to act by inhibiting cyclic adenosine monophosphate (cAMP) phosphodiesterase activity, which results in increased levels of cellular cAMP. Increased levels of cAMP are thought to increase calcium availability to the myocardial contractile components. These actions increase myocardial contractility and force of contractions (i.e., positive inotropic effect) without significant increases in heart rate and blood pressure. Some believe that the vasodilator action is the primary mechanism responsible for increasing myocardial performance. Vasodilation with amrinone may be the result of direct action by the drug on the vessels or may be caused by a reflex withdrawal of sympathetic tone following the improvement of myocardial function. Nonetheless, the primary effect of amrinone is an increase in myocardial contractility and stroke volume with a reduction in preload and afterload.
Pharmacokinetics Cardiovascular effects usually begin within 2 to 5 min and generally peak within 10 min at all doses. The duration of effect is dose-related. Following a 0.75-mg/kg bolus dose, the duration is about 30 min, while a 3-mg/kg dose will last approximately 2 h. Amrinone is metabolized in the liver, excreted in the urine, and has a Vd of 1.2 L/kg. In patients with normal renal function, amrinone has an elimination half-life of 3.6 h. In patients with CHF and/or hepatic or renal dysfunction, amrinone has a prolonged elimination half-life (average 5.8 h).
Common ED Indications Amrinone is indicated for increasing myocardial performance in the short-term management of CHF. Because of its adverse-effects profile, the drug should be used only when other therapies, such as diuretics, digoxin, and vasodilators, have failed. Amrinone has been studied in class III and IV CHF. It may serve as an alternative or adjunctive agent to dobutamine in the treatment of cardiogenic shock.
Dosing and Administration The initial dose is 0.75 mg/kg followed by a maintenance infusion at 5 to 10 Mg/kg per min. Amrinone should be administered as a slow direct intravenous injection (undiluted) over 2 to 3 min or as a continuous infusion diluted in 0.9 or 0.45% saline. Dextrose-containing solutions may result in a loss of the drug's activity. The total daily dose should not exceed 10 mg/kg. A second intravenous bolus injection may be given 30 min following the first dose if desired effects have not been achieved. Adjustments in the maintenance infusion should be titrated to clinical response.
Adverse-Effects Profile The most common adverse effects are thrombocytopenia (<100,000/mm3, in 2.4 percent), ventricular and supraventricular dysrhythmias (3 percent), hypotension (1.3 percent), and nausea (1.7 percent). Other adverse effects, which occur in fewer than 1 percent of patients, include vomiting, anorexia, fever, chest pain, and burning at the site of injection. Although rare, hepatotoxicity with amrinone has been reported. Acute marked elevations of hepatic enzymes along with clinical symptoms may suggest a hypersensitivity reaction, which would require prompt discontinuation of the drug.
MILRINONE Milrinone is a phosphodiesterase inhibitor with positive inotropic and vasodilator effects. It is similar to amrinone in its spectrum of action. Milrinone has a lower incidence of thrombocytopenia but a higher risk of cardiac dysrhythmias as compared with amrinone. Milrinone minimally slows AV node conduction time, which may speed the ventricular response in patients with atrial fibrillation or atrial flutter. Ventricular ectopy, ventricular dysrhythmias, and supraventricular dysrhythmias may also occur with milrinone, especially in high-risk patients.
Milrinone inhibits cAMP phosphodiesterase activity. Like amrinone, cAMP mediated increases in intracellular calcium permit the cardiac muscle to contract with increased force. Milrinone promotes improved diastolic function and vascular muscle relaxation. It is indicated for the treatment of CHF. The loading dose is 50 Mg/kg administered over 10 min, then a maintenance infusion at 0.375 to 0.75 Mg/kg per min (standard is 0.5 Mg/kg per min).
ATROPINE Actions Atropine sulfate, an antimuscarinic agent, enhances sinus node automaticity and AV conduction by blocking vagal activity; thus it has been termed a parasympatholytic drug. It has anticholinergic properties.
Pharmacokinetics The onset of action of atropine following intravenous, intramuscular, and endotracheal administration is rapid, with peak increases in heart rate occurring within 5 min. The half-life of atropine is 2 to 4 h or longer. Well absorbed and distributed throughout the body, atropine is metabolized in the liver and excreted in the urine.
Common ED Indications Atropine is the treatment of choice for increasing heart rate in hemodynamically unstable bradycardias (e.g., decreased heart rate with hypotension, altered mental status, "escape beats," and chest pain). Higher doses have been used in asystolic cardiac arrest, specifically if it is associated with increased vagal tone. It improves AV node conduction time in first degree and type I second degree AV block. Caution should be exercised with type II second degree and third degree AV block, since atropine may be associated with paradoxical slowing of the heart rate. The drug reverses cholinergic medications and toxins that cause a decrease in systemic vascular resistance, heart rate, and blood pressure. Additionally, atropine may reduce nausea and vomiting that occur as a result of morphine administration.
Dosing and Administration The dose of atropine for hemodynamically unstable bradycardia is 0.5-1.0 mg by rapid IV push, repealed q3-5 min until a desired heart rate is achieved or symptoms resolve. Do not administer less than 0.5 mg since lower doses are associated with paradoxical bradycardia. Bolus doses of 1 mg can be given for asystole and repeated once if necessary. A total dose of 3 mg (0.04 mg/kg) results in full vagolytic blockade in humans. It has been conventional practice to stop atropine administration when the total "vagolytic dose" has been given as outlined in standard ACLS teaching. This practice is appropriate when there is no response to atropine; further doses are unlikely to be effective. However, if a response is seen, there is no proscription to exceeding the "vagolytic" dose, if further dosing maintains the desired effect.
Atropine can be administered by intravenous push, intramuscularly, and via endotracheal tube. If given via the endotracheal tube, recommendations include a bolus of at least 1 mg at a time. No dilution is necessary when a preload syringe (1 mg/10 mL) is used. However, if the 1-mg/mL ampules are used, dilution with up to 10 mL of normal saline is recommended. It appears that absorption across tracheobronchial structure is good and substantial atropine levels are achieved within 10 min of dosing. The pediatric dose is 0.02 mg/kg with a minimum dose of 0.1 mg. Do not administer less than 0.1 mg since lower doses are associated with paradoxical bradycardia.
Adverse-Effects Profile Atropine is not indicated for bradycardia in hemodynamically stable patients. If it is administered, marked increases in heart rate can increase myocardial oxygen consumption, possibly inducing ischemia and precipitating ventricular tachydysrhythmias (including VT and VF). This is particularly true with doses greater than 0.5 mg. Doses less than 0.5 mg along with a therapeutic dose administered slowly can cause paradoxical bradycardia. This may be due to a central reflex stimulation of the vagus or a peripheral parasympathomimetic effect on the heart. There is concern by some about using atropine in AV block at the His-Purkinje level (type II AV block and third-degree block with new wide QRS complexes). Other effects that may occur include anticholinergic symptoms (e.g., blurred vision, dry mouth, CNS stimulation, hallucinations, mydriasis, tachycardia).
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