DOBUTAMINE HCL

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Premixed bags of dobutamine in 5% Dextrose Injection solutions may exhibit a pink color that, if present, will increase with time. This color change is due to slight oxidation of the drug, but there is no significant loss of potency. A sulfur dioxide odor may occur upon removal of the product from the overwrap container. This does not pose risk to the clinician or the patient.
Intravenous Administration
Dilution
-Concentrate for injection must be diluted with a compatible IV solution (e.g., 5% Dextrose Injection, 10% Dextrose Injection, 0.9% Sodium Chloride Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, 5% Dextrose and 0.45% Sodium Chloride Injection, Lactated Ringer's Injection) prior to administration.
-ASHP Recommended Standard Concentrations for Pediatric Continuous Infusions: 1,000 mcg/mL, 2,000 mcg/mL, or 4,000 mcg/mL.
-Maximum concentration should not exceed 5,000 mcg/mL.

Continuous IV Infusion

-Administer diluted solution by IV infusion using a controlled infusion device.
-Infuse into a large vein whenever possible. May administer via peripheral IV.
-Use caution to avoid inadvertent bolus administration or inadvertent interruption of the infusion, particularly during line changes, when flushing the line, or during syringe/bag changes.
-Do not administer dobutamine simultaneously with solutions containing sodium bicarbonate or strong alkaline solutions (incompatible). Solutions containing dextrose should not be administered through the same administration set as blood, as this may cause pseudoagglutination or hemolysis.
-Initiate infusion at a low rate and titrate every few minutes to reach the optimal dosage based on patient response. Dosage titration is guided by the patient's response, including systemic blood pressure, urine flow, frequency of ectopic activity, heart rate, and (whenever possible) measurements of cardiac output, central venous pressure, and/or pulmonary capillary wedge pressure.

Other Injectable Administration
Intraosseous Administration
NOTE: Dobutamine is not FDA-approved for intraosseous administration.
-During cardiopulmonary resuscitation, the same dosage may be given via the intraosseous route if IV access is unsuccessful or not feasible.

Dobutamine is arrhythmogenic, and treatment may cause arrhythmia exacerbation. In a study of 33 pediatric patients (ages 4 weeks to 17 years, mean = 5.1 years) receiving dobutamine 2.5 to 10 mcg/kg/minute for cardiogenic or septic shock, sinus tachycardia occurred in 2 patients and ventricular tachycardia and symptomatic chest pain (unspecified) occurred in 1 patient each. Seventy-eight percent of the adverse reactions in this study occurred at infusion rates of 7.5 mcg/kg/minute or more; in each case, a reduction in dose resolved the adverse reaction. Sinus tachycardia, with increases in the range of 5 to 15 beats per minute observed most commonly, results from the positive chronotropic effect of beta stimulation in a dose-related fashion. Heart rate increases of 30 beats/minute or more have been reported in approximately 10% of adult patients. Dobutamine has rarely caused ventricular tachycardia. Premature ventricular contractions (PVCs) likely occur secondary to the stimulatory effect of dobutamine on the conduction system of the heart and have been reported in approximately 5% of adult patients during dobutamine infusions. Angina, chest pain (unspecified), and palpitations have been reported in 1% to 3% of adult patients and occur secondary to the inotropic effects of dobutamine, which may lead to increased cardiac workload and, therefore, increased myocardial oxygen demand.

Dobutamine has the potential to cause hypertension or hypotension in susceptible patients depending on the clinical situation and status of the patient. In a study of 33 pediatric patients (ages 4 weeks to 17 years, mean = 5.1 years) receiving dobutamine 2.5 to 10 mcg/kg/minute for cardiogenic or septic shock, hypotension occurred in 3 patients and hypertension occurred in 1 patient. Seventy-eight percent of the adverse reactions in this study occurred at infusion rates of 7.5 mcg/kg/minute or more and resolved with a dosage reduction. Hypertension, with increases in systolic pressure of 10 to 20 mmHg, may be an indirect consequence of dobutamine-induced increased cardiac output. Systolic blood pressure increases of 50 mm Hg or more have been reported in approximately 7.5% of adult patients. Hypotension, although infrequent, may necessitate reduction or discontinuation of dobutamine. Reported clinical experience with dobutamine suggests that the incidence of significant hypotension is a function of dose. Rarely, intervention is required and reversibility is not immediate.

Dobutamine can rarely cause hypokalemia secondary to beta2 stimulation. Electrolyte disturbances can result in serious consequences in cardiac patients (e.g., proarrhythmia).

Case reports have been published describing myoclonia (e.g., muscle spasms) associated with the continuous infusion of dobutamine in patients with end stage renal disease. Although etiology of this reaction remains unclear, proposed mechanisms include an increase in dobutamine uptake by the central nervous system secondary to renal failure and an increase in the permeability of the blood-brain barrier caused by P-glycoprotein inhibition of concomitant medications.

Nausea has been reported in 1% to 3% of adult patients receiving dobutamine.

Rare, isolated cases of thrombocytopenia have been reported with the use of dobutamine.

In a study of 33 pediatric patients (ages 4 weeks to 17 years, mean = 5.1 years) receiving dobutamine 2.5 to 10 mcg/kg/minute for cardiogenic or septic shock, increased pulmonary wedge pressure with pulmonary edema occurred in 1 patient. Seventy-eight percent of the adverse reactions in this study occurred at infusion rates of 7.5 mcg/kg/minute or more and all responded to a reduction in dosage. Dyspnea has been reported in 1% to 3% of adult patients during dobutamine therapy.

Headache has been reported in 1% to 3% of adult patients during dobutamine therapy.

Injection site reaction, including phlebitis, is possible during dobutamine therapy. During inadvertent infiltration of dobutamine, local inflammatory reactions have been reported, and, rarely, skin necrosis may occur.

Hypersensitivity reactions, including rash, fever, eosinophilia, and bronchospasm, have been occasionally reported with dobutamine use. Some preparations of dobutamine contain sulfites, which may precipitate allergic/anaphylactoid reactions in susceptible individuals; such reactions appear to be more common in patients with asthma.

Stress cardiomyopathy has been reported with dobutamine in association with cardiac stress testing.

Dobutamine administration may produce symptomatic benefits in patients with acute decompensated heart failure; however, routine use of intermittent inotropic infusions has been shown to increase mortality in patients with chronic heart failure. The ACC/AHA guidelines for management of chronic heart failure in adults recommend that intermittent intravenous positive inotropic therapy has no proven value in patients with Stage C chronic heart failure; however, the guidelines suggest that continuous intravenous inotrope infusions may be considered for palliation of symptoms in patients with end-stage heart failure (e.g., Stage D).

Dobutamine is contraindicated in patients with idiopathic hypertrophic subaortic stenosis because the drug's strong inotropic effect is potentially harmful in the presence of such severe mechanical obstruction.

Do not administer dobutamine to patients with uncorrected hypovolemia; correct hypovolemia with volume expanders before initiating dobutamine.

Use dobutamine with caution in patients with cardiac arrhythmias such as atrial fibrillation and ventricular arrhythmias. Dobutamine increases atrioventricular conduction; patients with atrial fibrillation should be adequately digitalized before administration of dobutamine. Dobutamine may precipitate or exacerbate ventricular ectopic activity. Dobutamine may be associated with sinus tachycardia or premature ventricular contractions (PVCs) due to its stimulatory effect on cardiac conduction. Dobutamine rarely induces ventricular tachycardia; however it can cause a marked increase in heart rate in susceptible patients.

Use dobutamine with caution in patients with certain types of cardiac disease including acute myocardial infarction, unstable angina, or severe coronary artery disease because dobutamine can intensify or extend myocardial ischemia. Use dobutamine with caution in patients with hypertension as these patients are at risk for developing an exaggerated pressor response.

Dobutamine is contraindicated in patients with a hypersensitivity to dobutamine or any of its components. Formulations containing dextrose (e.g., premixed bags) may be contraindicated in patients with a known corn hypersensitivity. Some preparations of dobutamine contain sulfites; use these preparations with caution in individuals with sulfite hypersensitivity because these antioxidant compounds can cause allergic reactions, including anaphylaxis. This reaction appears to be more common in patients with asthma than non-asthmatic patients.

Dobutamine has been shown to increase cardiac output and systemic pressure in pediatric patients of every age group. In premature neonates, however, dobutamine is less effective than dopamine in raising systemic blood pressure without causing undue tachycardia, and dobutamine has not been shown to provide any added benefit when given to such infants already receiving optimal infusions of dopamine. In addition, because of variation in development, there is significant interpatient variability in response to dobutamine in neonates. Very preterm neonates are likely to have an attenuated reduction in systemic vascular resistance (SVR) compared to term neonates and therefore, experience a more pronounced increase in blood pressure. Titrate dosage carefully with close monitoring.

Monitor patients with renal failure carefully during dobutamine administration. Reports indicate that the continuous infusion of dobutamine in patients with end stage renal disease may produce myoclonia (e.g., muscle spasms). Although etiology of this reaction remains unclear, proposed mechanisms include an increase in dobutamine uptake by the central nervous system secondary to renal failure and an increase in the permeability of the blood-brain barrier caused by P-glycoprotein inhibition of concomitant medications.

Description: Dobutamine is primarily a beta1-selective intravenous inotrope, which also has some beta2- and alpha1-agonist properties, and is indicated for the short-term treatment of low output cardiac states. Although it is structurally similar to dopamine and other catecholamines, dobutamine is a synthetic compound with distinct pharmacologic properties, including potent inotropy and vasodilation. It has less alpha1-agonist and chronotropic effects relative to dopamine. Dobutamine increases myocardial contractility in a dose-dependent manner and is associated with decreased left ventricular filling pressures. Inodilators such as dobutamine may be used in pediatric patients with fluid-refractory septic shock and persistent hypoperfusion and cardiac dysfunction despite the use of other vasoactive agents. In general, increases in cardiac output and systemic pressure in pediatric patients are usually seen at infusion rates lower than those that cause significant tachycardia; however, in premature neonates, dobutamine is less effective than dopamine in raising blood pressure without causing tachycardia. Unlike dopamine, dobutamine does not affect dopaminergic receptors; however, urinary output can increase secondary to increased cardiac output. Dobutamine is FDA approved in pediatric patients as young as neonates.

General Dosing Information
-Administer adequate fluid resuscitation to hypovolemic patients prior to the administration of dobutamine.
-Titrate dobutamine to attain optimal patient response, as measured by heart rate and rhythm, blood pressure, urine output, cardiac output, and central venous or pulmonary wedge pressure.
-Tolerance may occur with prolonged infusions, resulting in alterations in dobutamine pharmacodynamics. Most clinical experience with dobutamine is short-term (several hours duration); however, infusions up to 72 hours have been given without the development of tolerance.

For the short-term inotropic treatment of low output states caused by congestive heart failure, cardiogenic shock, septic shock*, or after cardiac surgery:
Intravenous or Intraosseous* dosage:
Neonates: 0.5 to 1 mcg/kg/minute continuous IV/IO infusion; titrate every few minutes to clinical response. The usual dosage range is 2 to 20 mcg/kg/minute. Infusion rates higher than 20 mcg/kg/minute may produce tachycardia or ventricular ectopy. Because of variation in development, there is significant interpatient variability in response to dobutamine in neonates. Very preterm neonates are likely to have an attenuated reduction in systemic vascular resistance (SVR) compared to term neonates and, therefore, experience a more pronounced increase in blood pressure.
Infants, Children, and Adolescents: 0.5 to 1 mcg/kg/minute continuous IV/IO infusion; titrate every few minutes to clinical response. The usual dosage range is 2 to 20 mcg/kg/minute. Infusion rates higher than 20 mcg/kg/minute may produce tachycardia or ventricular ectopy. On rare occasions, infusion rates up to 40 mcg/kg/minute have been required to obtain the desired clinical response.

Maximum Dosage Limits:
-Neonates
20 mcg/kg/minute IV infusion; higher doses may be required in some clinical situations.
-Infants
20 mcg/kg/minute IV infusion; rarely, up to 40 mcg/kg/minute.
-Children
20 mcg/kg/minute IV infusion; rarely, up to 40 mcg/kg/minute.
-Adolescents
20 mcg/kg/minute IV infusion; rarely, up to 40 mcg/kg/minute.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments are not available; it appears that no dosage adjustments are needed. Titrate the dobutamine infusion rate to attain clinical goals.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments are not available; it appears that no dosage adjustments are needed. Titrate the dobutamine infusion rate to attain clinical goals.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Dobutamine is a direct-acting sympathomimetic. It is primarily an agonist at beta1-adrenergic receptors, with minor beta2 and alpha1 stimulatory effects. Clinical actions reflect both beta agonism by the (+) isomer and the alpha agonism by the less potent (-) isomer. Agonism at the beta1-adrenergic receptor predominates and increases myocardial contractility and stroke volume with modest chronotropic effects, resulting in increased cardiac output. The inotropic effects are dose-dependent. Dobutamine's secondary hemodynamic effects include decreases in systemic vascular resistance (afterload) and ventricular filling pressure (preload). Systolic blood pressure is generally elevated as a consequence of increased stroke volume, although diastolic blood pressure and mean arterial pressure are usually unchanged with usual doses in normotensive patients. Increased myocardial contractility results in increased coronary blood flow and myocardial oxygen consumption. Dobutamine has minimal effect on pulmonary vascular resistance. Unlike dopamine, dobutamine does not affect dopaminergic receptors, nor does it cause release of norepinephrine from sympathetic nerve endings. Urinary output can increase, however, secondary to increased cardiac output. Electrophysiologically, dobutamine can facilitate AV nodal conduction, particularly in patients with concomitant atrial fibrillation.

Pharmacokinetics: Dobutamine is administered via continuous IV infusion. Onset of action occurs within 2 minutes, although peak pharmacodynamic activity can be delayed up to 10 minutes. The plasma half-life of dobutamine is about 2 minutes. The drug is metabolized in the liver enzymatically by catechol-O-methyltransferase and by glucuronidation to inactive metabolites. Excretion occurs mainly by the kidney as the metabolites and conjugates. In general, increases in cardiac output and systemic pressure in pediatric patients are usually seen at infusion rates lower than those that cause significant tachycardia; however, in premature neonates, dobutamine is less effective than dopamine in raising blood pressure without causing tachycardia.

Affected cytochrome P450 isoenzymes: none


-Special Populations
Pediatrics
Neonates
The mean plasma clearance in 13 critically ill neonates 27 to 42 weeks gestational age (birth weight 850 to 4,900 g) receiving dobutamine 2.5 to 7.5 mcg/kg/minute IV was 90 +/- 38 mL/kg/minute. No association between clearance and gestational age or birth weight was found. Mean cardiac output increased by approximately 25% compared to baseline at the highest infusion rate; however, there was large interpatient variability in response (range 6% to 63% improvement).

Infants, Children, and Adolescents
In a prospective pharmacokinetic study, 11 stable critically ill patients 2 months to 14 years of age received dobutamine infusions. Infusion rates were sequentially increased, and patients received dobutamine for 25 minutes at each rate (0.05, 2.5, 5, 10, and 20 mcg/kg/minute) unless adverse reactions required discontinuation. The mean plasma clearance was 82 +/- 3 mL/kg/minute. Increases in cardiac index (CI) 10% or more were seen in 4 patients at the lowest infusion rate; a dosage increase from 10 to 20 mcg/kg/minute in 5 of 6 patients was associated with a mean increase in CI of 16%. Based on study results, the authors concluded that hemodynamic responses to dobutamine generally followed a log-linear relationship to dose. However, there was large interpatient variability in hemodynamic response to increasing dobutamine concentrations. Four patients were withdrawn from the study due to an increase in heart rate of more than 40%.