A 63-year-old female with a history of diabetes, prior myocardial infarction, and an ischemic cardiomyopathy with a left ventricular ejection fraction of 35% presents to the emergency department with shortness of breath with minimal exertion, as well as three pillow orthopnea, and paroxysmal nocturnal dyspnea. Six months prior to presentation, she was able to walk 3-blocks which has progressively worsened. One month prior she was started on Digoxin 0.125 mg in addition to her regimen of Metoprolol Succinate 25 mg, Lisinopril 2.5 mg, Spironolactone 25 mg, Aspirin 81 mg, and Plavix 75 mg (all daily), in addition to Metformin 1000 mg twice-a-day. In the emergency department, her initial vital signs show her to be afebrile, with a heart rate of 102 beats-per-minute, and a blood pressure of 90/66 mm Hg. Examination notes an elevated jugular venous pressure with a positive hepatojugular reflex. She has bibasilar crackles, an S3 on cardiac auscultation, and 1+ pitting edema with cool lower extremities. Chest x-ray demonstrates pulmonary edema, and an ECG shows sinus tachycardia with q-waves in leads V1-V3 (known from previous), and unchanged intervals and ST segments. Initial labs are notable for a sodium of 130 mmol/L, a serum creatinine of 1.6 mg/dL, a lactate of 3.1 mmol/L, and a troponin I of 0.93 ng/mL that remains unchanged 4-hours later. The managing team was confronted with a series of questions regarding the differential diagnosis, prognosis, and next management steps.

INTRODUCTION

Modern-day critical care cardiology is predicated on the ready use of hemodynamically active agents including inotropes and vasopressors. Vasoactive medications are far from advents of the 20th century. Ancient Egyptian texts suggest the use of sea onion as a treatment for edema, which was later noted to be a natural cardiac glycoside. Another cardiac glycoside-containing plant, foxglove, was also commonly used as early as the 1500s. Since then, the active ingredient has been extracted, and in 1785, Sir William Withering published his book on the account of foxglove, extolling its ability to treat edematous states, irregular heartbeats, and heart failure (HF). Its modern form is digitalis.² In 1893, Dr George Oliver, a British physician, began testing glandular extracts using his son as a research subject. He discovered adrenal extracts caused vasoconstriction. Later efforts on these same extracts led to the first vasopressor, suprarenin, later renamed as epinephrine. As epinephrine quickly became adopted by leading physicians, chemist Helmut Legerlotz synthetized what is now recognized as modern-day phenylephrine (1920s) and, by the 1940s, isoproterenol came to market via researchers in Germany. Isoproterenol quickly became a staple in treating acute cardiac disease. Isoproterenol functioned primarily through changes in chronotropy rather than inotropy. The hope for modified function of isoproterenol led to Ronald Tuttle and Jack Mills removing a side chain hydroxyl group that resulted in an agent with potent inotropic properties, now known as dobutamine (1975).³ Dobutamine continues to be a vital tool in the treatment of cardiogenic shock and is 1 of the 2 stable inotropes commonly employed in the critical care setting. The road to discovering therapies for HF and cardiogenic shock started many centuries ago, but it is only in the most recent decades that we have seen the advances that truly have allowed the natural history of decompensated HF and cardiogenic shock to change. The advent of inotropes, starting with dobutamine, and more recently, milrinone, has allowed the natural history of acute decompensated HF and cardiogenic shock to be more malleable, with more patients having the opportunity to survive critical cardiac illness either to recovery or to more advanced cardiac therapeutics.

In the following section, the most common inotropes and adjunct vasopressors will be discussed and subsequently will be applied to their appropriate clinical settings, specifically acute decompensated HF and cardiogenic shock.

PHARMACOLOGY

The inotropes used in support of patients with HF or cardiogenic shock have different mechanisms of action as well as pharmacologic properties that make them more, or less, ideal in certain situations (Figure 34-1 and Table 34-1). The breadth of evidence in support of these medications varies greatly between the differing classes. In this section, individual inotropes will be discussed as well as the evidence surrounding them (Table 34-2).

Digoxin

Clinical use of digitalis has existed for more than 200 years. Found in the foxglove plant, its properties have been extracted through teas and other formulations.⁴ Today it can be given by oral or parenteral routes, and acts by inhibiting the Na-K-ATPase pump in myocardial cells. This causes increased intracellular sodium, promoting greater sodium-calcium exchange, which then causes an increase in intracellular calcium concentration. This increased availability of calcium causes an improved myocyte contractile performance.⁵ Digitalis also acts as a vagotonic, upregulating the parasympathetic system. This is often seen in the reduction of atrioventricular nodal conduction and control of ventricular rates in atrial tachyarrhythmias. Short-term impact of digoxin has been assessed during right heart catheterization of patients in HF. Documented changes include an acute improvement in cardiac output, left ventricular (LV) stroke work index, and a decrease in pulmonary capillary wedge pressure (PCWP) and right atrial pressure both with rest or exercise.⁶ Long-term studies show that patients taking digoxin have symptom improvement and improved quality of life, but no meaningful change in mortality.⁷ Studies that looked at active removal of digoxin from a medical regimen showed clinical decompensation, suggesting that while survival is not improved, it is reasonable to remain on digoxin for quality of life and symptom control as withdrawal of the medication may result in clinical deterioration.⁸ The randomized controlled study (DIG trial) demonstrated no improvement in survival with digoxin though hospitalizations were decreased.⁹ In summation, digoxin improves symptoms and quality of life with no improvement in mortality as seen with modern-day neurohormonal blockade.⁹ In current practice, it is an adjunct to HF therapy, primarily for patients with systolic dysfunction, persistent symptoms, and atrial arrhythmias.

Dopamine

Dopamine is a vasopressor whose effect varies based upon the dose range administered. While often not a first-line agent, its lower potency allows this agent to be used in transition settings such as step-down units. At doses of 1 to 2 mcg/kg/min, dopamine impacts mostly the dopamine 1 receptors in the renal, mesenteric, cerebral, and coronary beds. This results in selective vasodilation and urine output may increase via augmentation of renal blood flow, which is greater than the increase in cardiac output achieved from this small dose. Natriuresis is also increased by inhibiting aldosterone and renal tubular sodium transport.^10-12 Despite the promising physiologic studies of dopamine mentioned above, the ROSE HF study showed no additional clinical benefit of adding dopamine to background of diuretics.¹³

As dopamine is further increased, to 5 to 10 mcg/kg/min, dopamine stimulates beta-1 adrenergic receptors and increases cardiac output, primarily by increasing stroke volume. At doses > 10 mcg/kg/min, dopamine stimulates mostly alpha adrenergic receptors resulting in vasoconstriction and increased systemic vascular resistance. As the dose increases, tachyarrhythmias increase as well. In cases of severe HF with evidence of clinical hypoperfusion and hypotension, doses are often started low to take advantage of the increase in inotropy while avoiding the deleterious effects of increased afterload and arrhythmic burden observed at higher doses.

Dopamine was compared with norepinephrine by the SOAP II investigators to help determine the appropriate vasopressor for the initial treatment of shock. In this randomized double-blind study, 1600 patients received either dopamine or norepinephrine for fluid refractory shock.¹ Primary outcome was the 28-day mortality with secondary outcomes including the occurrence of adverse events (arrhythmias, myocardial necrosis, limb ischemia, or infections). While the primary outcome showed no significant differences between the 2 groups, there were more arrhythmias in the dopamine group, specifically atrial fibrillation. Also, in the predefined cardiogenic shock subgroup, mortality was increased with dopamine (Figure 34-2).

Dobutamine

Dobutamine was first developed from modifying isoproterenol by Tuttle and Mills in 1975. The goal was to modify isoproterenol to alter the focused effect on positive chronotropy as well as to redirect the increase in cardiac output toward skeletal muscle due to its vigorous stimulation of beta-2 receptors in the periphery.³ Their result was a synthetic catecholamine that is both a beta-1 and partial beta-2 agonist. These effects work to increase myocardial contractility and thus, cardiac output, while decreasing left ventricular end diastolic pressure. Its effect on beta-2 receptors in peripheral blood vessels can cause vasodilation, which can be a useful secondary effect of decreasing cardiac afterload. As such, dobutamine has multiple mechanisms to increase cardiac output.

Its use is as a continuous infusion in patients with decompensated HF with signs of end-organ hypoperfusion. Using dobutamine in decompensated patients without end-organ dysfunction is contraindicated, as dobutamine has been associated with increased ventricular arrhythmias and mortality.^14,15 Its short half-life (2-3 minutes) is also ideal for an infusion that needs to reach therapeutic doses quickly. Its pharmacokinetics make it more ideal for patients with renal dysfunction as dosing does not have to be changed based on creatinine clearance.