Fellows
Vasoactive drugs in the ICU
By Armand Girbes
Jul 14, 2006 - 11:00:00 AM

Introduction

Pharmacological support of the cardiovascular system is a common therapeutic intervention in the Intensive Care Unit (ICU). Use of intravenous vasoactive drugs requires close monitoring of hemodynamic parameters, and patients requiring vasoactive drugs are commonly critically ill. Vasoactive drugs used in the ICU can be classified as follows: drugs for (i) improvement of myocardial contractility, (ii) increasing (systemic) vascular resistance, (iii) lowering (systemic) vascular resistance, (iv) decreasing preload, (v) increasing of heart rate, (vi) decrease of heart rate. Some vasoactive drugs, e.g. dopamine, exert combined actions on the cardiovascular system depending on the given dose. In this review aspects of cardiovascular support and commonly used vasoactive drugs will be discussed. Brief attention will be given to new vasoactive drugs such as the selective dopamine agonist fenoldopam and dopexamine. Discussion of vasoactive drugs specifically used in the treatment of ischemic heart disease and antiarrhythmic drugs is beyond the scope of this review.

The cardiovascular system

One of the fundamental roles of the cardiovascular system is to deliver oxygen to the tissues of the body, in quantities which exceed the tissues' demand for oxygen, thereby supporting aerobic metabolism. A decrease in oxygen delivery is initially compensated for by increased oxygen extraction, whenever possible. However, when oxygen delivery is insufficient to meet the requirement of oxygen, impaired function of vital organs results and metabolic acidosis with lactate formation develops. Oxygen delivery is defined as the total amount of oxygen delivered to the tissues per unit of time and may be calculated from the equation:

      Oxygen delivery = Cardiac Output x Arterial Oxygen Content.

This equation emphasizes the importance of Cardiac Output, which is the product of heart rate and stroke volume. It is important to realize that stroke volume can itself be influenced by the heart rate. An increased heart rate shortens the filling time (diastole), whereas the duration of systole remains relatively unchanged. Additionally, an increased heart rate carries the risk of provoking myocardial ischemia.

Stroke volume is determined by preload, afterload and the contractile state of the myocardium. Modification of these factors provides the basis for the hemodynamic support of the critically ill patient.

The role of preload and fluid administration

Manipulation of preload, for example by the administration of intravenous fluids, is able to increase stroke volume without changing heart rate or afterload, and so myocardial oxygen requirements are scarcely changed. It is very important to realize that optimization of preload remains the most effective way of increasing cardiac output, and this should always be attempted before the introduction of inotropic drugs is considered. However, excessive filling of the ventricle may lead to dilatation of the ventricle with a subsequent fall of stroke volume. Therefore intravenous fluids should be administered with care, observing the resultant changes in arterial blood pressure, central venous pressure and/or capillary wedge pressure and urine output in an attempt to determine the optimum filling pressures or preload for a particular patient at a particular time.

Commonly used inotropic drugs

Dobutamine

      Dobutamine, a synthetic catecholamine, is predominantly an agonist at ß1-receptors although it has moderate agonist effects on ß2-adrenergic receptors and weak effects on a1-adrenergic receptors, but no effects on dopamine (DA) receptors. The drug exists as a racemic mixture of two stereoisomers. The a1-adrenergic activity is due to the levoisomer and the ß-adrenergic activity is due to the dextroisomer. Dobutamine increases cardiac output mainly through stimulation of ß1-receptors, located on myocardial cells. An additional increase in cardiac output may be due to slight arterial vasodilation as a result of ß2-receptor stimulation. Coronary perfusion increases as a result of an increased cardiac output. Dobutamine is mainly used to increase cardiac output and can be given when this is a desirable goal of therapy and adequate preload has been achieved. It is the inotropic drug of choice for acute management of heart failure. Additionally, short periods of dobutamine infusion may produce beneficial effects on cardiac performance for up to 4 weeks. A potentially undesirable effect of dobutamine is to increase the heart rate, thus increasing myocardial oxygen demand(1,2).

Dopamine

Dopamine, a naturally occurring precursor of norepinephrine, is extensively used in the intensive care setting(3,4). Dopamine exerts a complicated influence on the cardiovascular and renal system which is dose dependent. This is due to the fact that dopamine stimulates different types of adrenergic receptors: not only a- and ß-adrenergic but also specific dopamine receptors (5). In doses of 1-4 mg/kg/min, nicknamed "renal dose", the predominant effect of dopamine is a marked increase of renal plasma flow, glomerular filtration rate and sodium excretion. This is mainly caused by stimulation of dopamine-receptors. However, also in these doses effects on cardiac output are present. Therefore the use of the nomenclature "renal dose" should be avoided. In doses of 4-10 mg/kg/min dopamine the positive inotropic effects become more apparent, primarily as a result of ß-(1)-receptor stimula­tion. In doses above 10 mg/kg/min dopamine induces vasoconstric­tion and positive chronotro­pism as a result of predominant a-adrenergic and ß-adrenergic effects, respectively. The scheme sketched above is of course an oversimplification. The observed effect of dopamine infusion is not entirely predictable as it is dependent upon the complex interactions occurring between the wide variety of receptors being stimulated.

Dopamine receptors are present at various sites of the body, not only in the Central Nervous System (CNS), but also outside the CNS, the so called peripheral dopamine receptors. These receptors are divided in two types: postsynaptic DA1, and (presynaptic) DA2 receptors. DA1 receptors are located in blood vessels and in the proximal tubule of the kidney (6). Stimulation induces vasodila­tion and natriuresis (7‑11). The DA2 receptors are situated prejunctionally on sympathetic nerve terminals and in the adrenal gland. Stimulation of DA2-dopamine receptors results in inhibition of norepinephrine release and inhibition of aldosterone secretion (12,13).

Dopamine may be indicated in several clinical situations. In our Intensive Care Unit dopamine is commonly the first inotropic drug to be used in shocked patients with appropriate filling pressures. In heart failure it can easily be combined with dobutamine. In septic patients the dose of dopamine can be increased in order to induce vasoconstriction.

      It has been suggested that the ability of dopamine to selectively dilate the renal vasculature may help to protect the kidney from further toxic or ischemic insults. However, this renal-protective role of dopamine is so far unproved.

Norepinephrine

Norepinephrine, a naturally occurring catecholamine, is a potent adrenergic vasoconstrictor, with predominant a1-receptor stimulating activity. It is mainly used to increase perfusion pressure in situations where a generalized reduction of vascular resistance reduces perfusion pressure to vital organs, such as in septic shock. Adverse effects include severe peripheral vasoconstriction, resulting in tissue ischemia, e.g. renal failure. However, recent studies suggest that in severe septic shock, where the advantage of increasing perfusion pressure is more important, norepinephrine improves renal function(14). Norepinephrine is contraindicated in hypotension associated with (severe) peripheral vasoconstriction.

Epinephrine

Epinephrine, also a naturally occurring catecholamine, is a combined a- and ß-agonist.

Alpha effects are mainly observed at higher doses. Epinephrine is the drug of choice in cardiopulmonary arrest and in the treatment of anaphylaxis. Since it is also absorbed through airway mucosa, it can also be administered in emergency situations via the endotracheal tube. Adverse side effects include acute myocardial infarction, arrhythmias, tissue hypoperfusion and renal failure.

Isoprenaline

Isoprenaline is mainly a ß1- and ß2-agonist and is, after a trial of atropine, the drug of choice for bradyarrhythmias, particularly in anticipation of inserting an artificial cardiac pacemaker. Adverse effects are comparable to epinephrine.

New vasoactive drugs

Dopexamine

Dopexamine is a new ß2-receptor stimulating drug with additional moderate DA1- and DA2- receptor stimulation activity. Intravenous administration results in a dose related peripheral vasodilation which is accompanied by an increase of cardiac index and heart rate. However, dopexamine induces an increase of plasma norepinephrine and plasma renin activity. Furthermore, dopexamine inhibits neuronal catecholamine uptake, which may contribute to the rise of norepinephrine, leading to a positive inotropism and chronotropism. These properties make it an unattractive drug for the treatment of heart failure.

Considering its renal effects dopexamine possibly increases GFR, renal plasma flow and sodium excretion. However, detailed studies on its renal effects in man are not available(3).

At higher doses no vasoconstriction is observed, unlike dopamine, because dopexamine does not stimulate directly a-adrenergic receptors. The dose dependent DA1-receptor agonist activity of dopexamine is approximately 33% of that of dopamine. The hemodynamic effects of dopexamine are mainly the result of its vasodilatory properties. Caution is required in view of the dose-dependent increase of heart rate and therefore the lowest possible dose should be administered. At this moment there seems to be no reason to use dopexamine in preference to the other commonly used vasoactive drugs in intensive care patients. In view of it's vasodilating properties, dopexamine might be used for the treatment of severe hypertension. However, studies with dopexamine for the treatment of hypertensive crisis are lacking.

Phosphodiesterase inhibitors

Stimulation of ß-adrenergic receptors results in an increase in cyclic AMP within the myocardial cells, which results in an increased contractility. The hydrolysis of cyclic AMP to form 5'AMP is catalyzed by the enzyme phosphodiesterase. A more recently introduced group of drugs, the selective phosphodiesterase inhibitors (PDI) competitively inhibit this enzyme, resulting in an increase in the intracellular availability of cyclic AMP. PDI induce positive inotropism, but also peripheral vasodilation. In the Netherlands, enoximone, a imidazole derivate, and milrinone are available for intravenous use. These drugs have been shown to increase cardiac output with a concomitant fall in systemic vascular resistance. Since this class of drugs produces both inotropism and vasodilation, they are called inodilators. The inotropic effects are seen within minutes of starting their administration. Though these drugs are not first line drugs, they may be considered in selective cases, e.g. when other drugs have failed, and/or for bridging the waiting-period for heart transplantation. Combination with ß1-receptor agonists is possible and rational. Possible adverse effects include worsening of myocardial ischemia, thrombocytopenia,fever, hepatic dysfunction and arrhythmias. Long-term treatment with oral PDI in patients with chronic heart failure has shown an increase in mortality(15,16). Therefore these oral compounds have been withdrawn by the manufacturers.

Ibopamine

Ibopamine, a prodrug, is the di-isobutyryl ester of methyl-dopamine (epinine) and is de-esterified to epinine after oral administra­tion. Epinine, stimulates a-, ß-adrenergic and DA1- and DA2-dopamine receptors. Ibopamine has been used in the treatment of chronic heart failure and has shown to improve hemodynamic parameters and exercise tolerance in these patients(17). Additionally, it influences neurohumoral activation favorably and improves renal function slightly (18).

We have recently observed six otherwise stable patients who were dependent on intravenous dopamine infusions, despite adequate filling after a prolonged stay in our ICU. In these patients oral ibopamine was able to substitute intravenous dopamine. This allowed removal of the central venous catheter and referral to the ward. This observation might therefore suggest a role for ibopamine substitution in otherwise stable patients.

Fenoldopam

Fenoldopam is a both intravenously and orally active DA1 agonist and stimulates DA1 receptors selectively. The serum halflife time of fenoldopam is about 10 minutes. Administration of fenol­dopam in man induces a fall in blood pressure, systemic and renal vasodilation and an increase of diuresis and sodium excretion. In patients with heart failure fenoldopam induced a fall in blood pressure, pulmonary capillary wedge pressure and mean pulmonary pressure. The systemic vascular resistance decreased and the cardiac output increased. However, the right filling pressures did not decrease (3). Several studies indicate that intravenous fenoldopam possesses an advantageous profile in the treatment of hypertensive crises or severe hypertension, when compared to nitroprusside (19,20). Fenoldopam controls the blood pressure to a similar extent and can be as easily titrated, but is - at higher doses - not toxic, and increases furthermore natriuresis and renal plasma flow. However, the effects mentioned above are accompanied by an increase of Plasma Renin Activity (PRA), plasma aldosterone concentration (PAC) and norepinephrine. This reflects activation of the Renin-Angiotensin-Aldosterone-System (RAAS) and sympathetic drive may blunt the blood vasodilatory and natriuretic effect of fenoldopam. No severe adverse drug reactions have been reported so far but flushes, palpitations and headache may occur.

Vasodilating drugs

Nitroprusside

Nitroprusside, a non-specific vasodilator, acts on the arterial and venous wall. A rapid action after onset of intravenous infusion and a short elimination half-life make the drug easy to titrate. Nitroprusside is the drug of choice in the treatment of hypertensive crisis (2,21). Additionally, it may be of value in acute left ventricular failure without hypotension and in acute myocardial infarction with septum or papillary muscle rupture. The metabolism of nitroprusside yields cyanide and thiocyanate and cyanide toxicity is a serious possible adverse effect of nitroprusside administration. This may occur especially in states of renal function loss.

Therapy of nitroprusside toxicity consists of stopping the drug and administration of vitamin B12.

Nitroglycerin

Nitroglycerin relaxes smooth muscle of arteries and veins and is at lower doses a mainly venous vasodilator. Venodilation will result in decreased left and right ventricular enddiastolic pressures. Systemic vascular resistance is usually unaffected. Nitroglycerin can therefore be used to reduce preload, besides it's specific anti-anginal indication. Adverse effects include the development of tolerance, methemoglobinemia, and heparin resistance. Additionally, it may cause increased shunting in patients with pulmonary edema(2).

Oxygen dependence

Shoemaker et al. and other groups have reported an improved outcome in septic and high-risk surgical patients which was achieved by increasing cardiac output and thus increasing oxygen delivery(22‑24). The increase in (calculated) oxygen consumption as a response to an increase in oxygen delivery is called oxygen dependence. Oxygen consumption is calculated by the equation:

      Cardiac Output x Arteriovenous oxygen content difference.

Patients treated with the aim of maximizing oxygen consumption are thought to have better outcomes. The administration of dobutamine with the aim of increasing cardiac output and thereby oxygen delivery is an important therapeutic tool in this concept. However, both the concept of oxygen dependence and the improved outcome have been questioned by other investigators (25,26). Ronco et al. measured oxygen consumption by analysis of inspiratory and expiratory gas. These investigators suggest that the correlation of oxygen consumption and delivery is due to a systematic error and bias: use of the same parameters for calculation of both oxygen consumption and delivery will always result in a correlation (26).

Table 1           Inotropic drugs and catecholamines: action on various adrenergic receptors is indicated. An indication for the degree of receptor stimulation is given. Most of these are dose-dependent.

                        * = for higher doses

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