Rationale for Using Inotropic Therapy in the Critically Ill

On can consider two objectives for inotropic therapy in the critically ill: (1) to restore an adequate cardiac output through an improvement in cardiac function in patients with low blood flow related to reduced myocardial contractility and (2) to achieve supranormal cardiac output values to prevent or reduce complications in some high-risk situations; in this setting, inotropes could be given after volume resuscitation, even in patients with normal myocardial contractility.

Use of Inotropes for Reversing Impaired Myocardial Contractility

The first category of situations where inotropic therapy is generally considered includes cardiogenic shock, acute heart failure, or acute exacerbation of chronic heart failure. However, although the use of such therapy in these clinical conditions seems logical on a purely pathophysiologic basis, no demonstration of a beneficial impact on morbidity and mortality can be found in the literature. Moreover, almost all the commercially available inotropes have been shown to be associated with increased mortality rates when given on a long-term basis to patients with chronic heart failure. It has been postulated that the long-term use of inotropes may lead to deterioration of left ventricular function through acceleration of myocardial cell apoptosis.¹ Additionally, the beneficial effects on mortality of agents known to have negative inotropic effects, such as β-blockers, is now well established in patients with chronic heart failure.^2,³ Therefore, inotropic therapy is generally reserved for patients with cardiogenic shock or for patients with advanced heart failure whose condition is refractory to standard therapy including diuretics, digoxin, β-blockers and angiotensin-converting enzyme (ACE) inhibitors. Under these conditions, clinicians can expect short-term positive effects of intravenous (IV) inotropic therapy, allowing cardiovascular stabilization. In patients with refractory heart failure who are candidates for cardiac transplantation, this therapy can be used as a bridge to transplantation. In those with potentially reversible causes of acute heart failure (such as myocardial infarction or acute myocarditis), short-term inotropic therapy must be considered as an appropriate bridge to coronary revascularization or recovery. The development of bedside echocardiography in the intensive care unit (ICU) should allow appropriate use of inotropic therapy, since this method provides a more accurate assessment of systolic cardiac function than traditional invasive methods like pulmonary artery catheterization.

Use of Inotropes for Achieving Supranormal Levels of Oxygen Delivery

High-Risk Surgical Patients

The concept of attempting to achieve supranormal hemodynamic endpoints emerged from studies in high-risk surgical patients. In a prospective study in high-risk patients undergoing surgery, Shoemaker et al. showed that the use of supranormal hemodynamic values as therapeutic endpoints was associated with a reduction in mortality from 33% to 4%.⁴ In the protocol group, dobutamine and dopamine were given as inotropic drugs—even in the absence of evidence of reduced cardiac contractility—when volume resuscitation (and packed red blood cells if necessary) failed to achieve supranormal values of myocardial oxygen delivery (DO₂)⁴ (DO₂ > 600 mL/min/m²). In other randomized studies performed in high-risk patients undergoing surgery, the deliberate perioperative increase in DO₂ above supranormal values using fluid infusion and various inotropic drugs (dobutamine, dopamine, epinephrine, dopexamine) were associated with decreased mortality and postoperative complications.⁵ It remains unclear, however, whether the benefits were related to the increased DO₂ per se or to other antiinflammatory effects of catecholamines.⁶ The issue of drug dose is also essential. A recent meta-analysis has suggested that in the setting of major surgery, dopexamine at low doses but not at high doses could improve outcome.⁷ From all these findings, it is reasonable to consider the increase of cardiac output and DO₂ towards supranormal values during the perioperative period in high-risk patients undergoing elective major surgery.

Critically Ill Patients

Whether this therapeutic approach could also be applied to patients admitted to the ICU for established acute illnesses has been a matter of debate. On the one hand, a pathologic myocardial oxygen consumption/oxygen delivery (VO₂/DO₂) dependency, presumably due to impaired oxygen extraction capabilities, has been reported in various categories of acute illnesses such as sepsis ⁸ and acute respiratory distress syndrome.⁹ Such a phenomenon was reported to correlate with the presence of increased blood lactate, a marker of global tissue hypoxia,⁸ and to be associated with a poor outcome.¹⁰ This so-called pathologic oxygen consumption/supply dependency would incite the clinician to increase DO₂ towards supranormal values to overpass its critical level. However, such an aggressive therapeutic approach has been seriously questioned since the publication of randomized clinical trials performed in patients with acute illnesses that did not demonstrate any benefit from deliberate manipulation of hemodynamic variables toward values higher than physiologic values.^11,¹² In one of these studies, the mortality rate was even higher in the group of patients assigned to receive an aggressive treatment aimed at achieving supranormal values of DO₂.¹¹ It was postulated that deleterious consequences of the use of high doses of dobutamine in patients of the protocol group were responsible for the increased mortality. It has to be noted that (1) the patients of the protocol group received high doses of the inotropic agent despite the absence of evidence for an altered contractility, and (2) in most of these patients, the aggressive inotropic support failed to achieve the target value of VO₂ (170 mL/min/m²). The analysis of the subgroup of septic patients of this study showed that the survivors were characterized by ability to increase both DO₂ and VO₂ regardless of their group of randomization.¹³ The non-survivors were characterized by an inability to increase their VO₂ despite the increase in DO₂, suggesting a more marked impairment of peripheral oxygen extraction in non-survivors than in survivors.¹³ In addition, the ability to increase cardiac output and DO₂ was also significantly reduced in non-survivors in comparison with survivors, suggesting a decrease in cardiac reserve in those patients who will die.¹³ This is not a surprising finding, since the degree of myocardial dysfunction in septic shock correlates with increased risk of death. In this regard, it has been suggested that the response to a dobutamine challenge could have a prognostic value in septic patients. Indeed, in two prospective studies, survivors were able to increase both VO₂ and DO₂ in response to dobutamine, while non-survivors were unable to increase either DO₂ or VO₂ or both.^14,¹⁵

From all the results of randomized controlled studies, the deliberative attempt to achieve supranormal hemodynamic targets in the general population of critically ill patients is no longer recommended.^16,¹⁷ However, in the early phase of septic shock when blood flow and DO₂ are generally low, an aggressive hemodynamic therapy including inotropes, aimed at rapidly normalizing DO₂, was demonstrated to result in a better outcome in a randomized control trial.¹⁸ Thus, in the early phase of septic shock and maybe in other acute illnesses, it could be essential to rapidly restore normal global blood flow to avoid further deleterious consequences of systemic hypoperfusion. In later stages of the disease, with inflammatory processes and organ dysfunction already developed, no evidence of benefit from a further increase in DO₂ has been shown. However, it seems likely that cardiac output should be kept in the normal range by using volume and/or inotropes to prevent worsening of the insult.

Pharmacologic Properties of Inotropic Agents

Different inotropic drugs are available. Some of them act on adrenergic receptors located at the surface of cardiomyocytes; others exert their effects within the myocardial cell.

Adrenergic Signaling

Natural as well as synthetic catecholamines enhance the Ca²⁺ cytosolic amount, which is directly related to the force of contraction (Figure 92-1). Ca²⁺ fixes on the troponin C Ca²⁺-specific binding site, inducing a conformational change that leads to the fixation of the myosin head to the actin filament. Hydrolysis of the adenosine monophosphate (ATP) molecule located on the myosin head to adenosine diphosphate (ADP) simultaneously induces the flexion of the myosin neck and the shortening of the contractile apparatus.

Figure 92-1 Mechanisms of action of inotropic agents at the cellular level.

Schematic representation. β-Agonist agents fix the β receptor and stimulate formation of cyclic AMP (cAMP) from AMP through adenylate cyclase. Cyclic AMP activates protein kinase A (PKa), which provokes extrusion of Ca²⁺ from the sarcoplasmic reticulum into the cytosol through phosphorylated ryanodine receptors. Ca²⁺ fixes troponin C (Tn_c) and finally activates fixation of actin on myosin filaments. Phosphodiesterase (PDE) inhibitors also increase cAMP concentration by inhibiting its degradation. The mechanism by which Ca²⁺ sensitizers increase inotropism is enhancement of troponin C sensitivity for Ca²⁺. Cardiac myosin activators increase activity of the ATPase of myofibrils, increasing the contractile force of cardiomyocytes without increasing the amount of ATP molecules required for contraction. Istaroxime is a new drug that inhibits Na⁺/K⁺-ATPase, increasing activity of sarcoendoplasmic reticulum calcium ATPase pump and increasing reuptake of Ca²⁺ by the sarcoplasmic reticulum.

A rapid overview of the physiologic response to adrenergic-receptor stimulation is essential to understand the pharmacologic properties of these drugs. Receptors of the adrenergic system are classed as α₁, α₂, β₁, β₂, and dopaminergic receptors. Activation of the β₁ receptors, and to a lesser degree the α₁ receptors, is responsible for the inotropic effect of adrenergic agents.

Pharmacologic Properties of the Inotropic Agents Used in Clinical Practice

Epinephrine

Epinephrine is the main physiologic adrenergic hormone of the adrenal medullar gland. It is a potent stimulator of α, β₁, and β₂ receptors. The α-adrenergic effect is responsible for a marked arterial and venous vasoconstriction. Epinephrine increases systolic arterial pressure, but its effect on vasculature is partly counteracted by the β₂-mediated vasodilation. The diastolic blood pressure is thus only slightly affected by epinephrine, and the increase in mean arterial pressure (MAP) is less than with norepinephrine.

Through cardiac β₁ stimulation, epinephrine increases heart rate and inotropism. The combination of the latter effects and the α-mediated venous constriction promoting venous return and cardiac preload results in increase in cardiac output. Epinephrine also facilitates ventricular relaxation and enhanced coronary blood flow through the increase in myocardial VO₂.

Norepinephrine

Norepinephrine is the physiologic mediator released by the postganglionic adrenergic nerves. It is a potent α- and β₁-adrenergic agonist, but it has little activity on β₂ receptors. Through its α-adrenergic effect, norepinephrine induces potent arterial and venous constriction. It increases systolic as well as diastolic blood pressure, left ventricular afterload, venous return, and cardiac filling pressures. The β₁ stimulation results in a positive inotropic effect and an increase in stroke volume. However, the chronotropic effect is counteracted by baroreflex stimulation following vasoconstriction. Consequently, the heart rate is unchanged or reduced, and the cardiac output can be unchanged. Coronary blood flow is enhanced by norepinephrine because of coronary vasodilation secondary to enhanced cardiac metabolism and because of normalization of diastolic blood pressure when low.

Dopamine

Dopamine is the immediate physiologic precursor of norepinephrine and epinephrine. The cardiovascular effects of dopamine are mediated by several types of receptors that are activated at different levels of dopamine concentration and by norepinephrine produced by the transformation of dopamine.

At low rates of administration (<5 µg/kg/min), dopamine activates D₁ receptors located in renal, mesenteric, cerebral, and coronary vessels and induces vasodilation without affecting arterial blood pressure. At higher and intermediate rate of administration (5-10 µg/kg/min), dopamine predominantly stimulates the β₁-adrenergic receptor and thus enhances inotropism and increases heart rate. At such rates of infusion, dopamine increases systolic blood pressure without altering diastolic blood pressure, because stroke volume is enhanced and arterial vascular tone only slightly altered. Norepinephrine resulting from dopamine transformation contributes to these cardiovascular effects. At higher rates of administration (10-20 µg/kg/min), dopamine predominantly activates vascular α₁-adrenergic receptors and induces arterial and venous vasoconstriction, counteracting the D₁-receptor mediated vasodilation. This vasoconstriction increases arterial blood pressure, venous return, and cardiac filling pressures. At higher rates of administration, dopamine hemodynamic effects are similar to those of norepinephrine.

Dobutamine

Dobutamine is a synthetic adrenergic agonist derived from dopamine. Its effects on adrenergic receptors are complex but do not result from endogenous transformation to norepinephrine. Dobutamine simultaneously activates different adrenergic receptors with some opposite effects. In fact, the clinically used drug is a racemic mixture of a (−) enantiomer, activating α₁-adrenergic receptors, and a (+) enantiomer, activating β₁ and β₂ receptors. The α₁– and β₁-adrenergic stimulation results in inotropic and chronotropic effects. Dobutamine exerts no intrinsic vascular effect, because the vasoconstriction induced by α₁ stimulation is counteracted by the β₂ vasodilating effect.

Dopexamine

Dopexamine is a synthetic catecholamine inducing β₂ and dopaminergic receptor activation, with no effect on α-adrenergic receptors and a weak direct effect on β₁-adrenergic receptors. It also exerts indirect effects through inhibition of neuronal reuptake of norepinephrine. Its administration induces vasodilation and inotropic effect with substantially increased stroke volume.

Isoproterenol (or Isoprenaline)

Isoproterenol (or isoprenaline) is a potent synthetic β-adrenergic agonist with a very low affinity for α-adrenergic receptors. Through its potent β₂ vasodilating effect it induces a fall in diastolic and mean blood pressure, whereas systolic blood pressure is increased owing to the increase in stroke volume related to its β₁-adrenergic activation. The combination of the latter effect and the marked increase in heart rate leads to enhanced cardiac output. The resulting increase in myocardial VO₂ is not compensated by coronary blood flow enhancement, so isoproterenol infusion may lead to myocardial ischemia, especially if there is preexisting coronary artery disease. Because of its proischemic and hypotensive effects, isoproterenol is no longer used as an inotropic agent in clinical practice in the absence of bradycardia.

Phosphodiesterase Inhibitors

Despite the major role of catecholamines in the management of critically ill patients with inadequate cardiac output, problems such as tachycardia, arrhythmias, increased myocardial VO₂, excessive vasoconstriction, or loss of effectiveness with prolonged exposure to β-agonists may occur. Thus, other inotropic drugs such as phosphodiesterase inhibitors (milrinone and enoximone) have been proposed for the management of myocardial dysfunction. These synthetic drugs inhibit the peak III isoform of phosphodiesterase, which catalyses cAMP (see Figure 92-1). By increasing intracellular cAMP concentration, they induce a potent vasodilation of arterial and venous systems through relaxation of vascular smooth muscle. The left ventricular preload is reduced to a greater extent than with dobutamine. At the cardiac level, phosphodiesterase inhibitors induce an inotropic effect similar to that induced by dobutamine. The heart rate is increased only at high rates of administration. The resulting effect is an increase in cardiac output. Because the enhancement of cAMP intracellular concentration also promotes the reuptake of Ca²⁺ by the sarcoplasmic reticulum, phosphodiesterase inhibitors facilitate ventricular relaxation. Finally, since β-agonists exert their action by increasing the production of cAMP, phosphodiesterase inhibition could enhance their adrenergic effects. This is the pharmacologic basis for the synergic association of β-agonists and phosphodiesterase inhibitors.

Calcium Sensitizers

Calcium sensitizers increase the sensitivity of troponin C for Ca²⁺ and hence the force and duration of the cardiomyocytes’ contraction (see Figure 92-1). To date, levosimendan is the only calcium sensitizer approved for clinical use. The advantage of levosimendan over classical inotropes would be to increase the force of contraction without enhancing the influx of Ca²⁺ into the cytosol and thus without increasing the risk of arrhythmias related to this ionic alteration. Some degree of phosphodiesterase III inhibitory activity probably also contributes to the inotropic effect of these drugs. It also induces vasodilation by opening ATP-dependent K⁺ channels.¹⁹

Cardiac Myosin Activators

Cardiac myosin activators belong to a new class of inotropes. They increase the activity of the ATPase of the myofibrils, increasing the contractile force of the cardiomyocytes without increasing the amount of ATP molecules required for contraction—that is, without increasing the myocardial VO₂.²⁰ Additionally, these substances increase the cardiac contractile force without the potentially deleterious increase in intracytoplasmic Ca²⁺ concentration. Cardiac myosin activators have been tested in animal studies in which their inotropic properties have been well demonstrated. Pharmacologic studies in humans are ongoing.

Istaroxime

Istaroxime is a new drug that inhibits the Na⁺/K⁺-ATPase, increasing the activity of the sarcoendoplasmic reticulum calcium ATPase pump. It induces some inotropic and lusitropic effects.²¹ In animals, istaroxime was demonstrated to decrease the end-diastolic volume of the left ventricle and to increase the left ventricular ejection fraction. In patients with decompensated heart failure without hypotension, istaroxime decreased the pulmonary artery occlusion pressure and improved the diastolic function of the left ventricle.²² This drug is still under clinical evaluation.

Decrease in β-Adrenergic Response

It is well recognized that response to β-adrenergic stimulation is decreased in chronic cardiac failure. This may be a response to increased activity of the sympathetic nervous system, which may itself be a response to reduced cardiac output. Therefore, this negative retrocontrol of the β-adrenergic response could act as a protection against excessive adrenergic stimulation. The cellular mechanisms involved are down-regulation of β₁-adrenergic receptors and stimulation of the G_i protein of the adenylcyclase system. The decrease in β₁-adrenergic receptors could result from a decrease in β-adrenergic receptor messenger RNA and to an increased internalization and degradation of these receptors. These latter mechanisms are mainly related to the phosphorylation of β₁-adrenergic receptors by the β-adrenoreceptor kinase, which is activated. The high level of nitric oxide (NO) production during heart failure also contributes to attenuation of β-adrenergic response. The effects of exogenous catecholamines during exacerbations of chronic heart failure can thus be reduced.

Similarly, there is evidence for a decreased responsiveness of the myocardium to β-adrenergic stimulation during septic shock.²³ This may be explained by the inhibition of adenylcyclase activation due to an overexpression of G_i protein²⁴ at the gene level.²⁵

Hemodynamic Effects of Inotropic Agents in Critically Ill Patients

Effects on Cardiac Output

Dobutamine and Dopamine

Dobutamine and dopamine are the β-adrenergic agents most widely used in critically ill patients when an increase in cardiac output through an increase in myocardial contractility is desired.

In patients with acute heart failure, the effects of these two agents were compared in a crossover trial.²⁶ Whereas dobutamine (2.5-10 µg/kg/min) increased cardiac output through an increase in stroke volume in a dose-response fashion, dopamine increased stroke volume and cardiac output at 4 µg/kg/min but not at higher doses, presumably because of an increase in left ventricular afterload. It was also reported that pulmonary artery occlusion pressure decreased with dobutamine while it increased with dopamine. Similar findings were observed in patients with respiratory failure in whom dopamine also increased the left ventricular end-diastolic volume measured using isotopes, while dobutamine did not.²⁷ This suggests an increase in left ventricular preload only with dopamine.

In patients with septic shock, in addition to hypovolemia, severe systemic vasodilation is associated with a variable degree of depressed myocardial contractility.²⁸ Dopamine at median or high doses has been proposed as one of the first-line catecholamines when arterial pressure remains low despite adequate volume resuscitation,¹⁹ as it can exert both an α-mediated increase in arterial tone and a β-mediated increase in myocardial contractility. However, it was reported that restoration of an adequate MAP with dopamine was mainly produced by the increase of cardiac output through an increase in stroke volume and, to a lesser extent, increase in heart rate; whereas minimal effects on systemic vascular resistance (SVR) were observed despite relatively high doses of this agent.²⁹ Dopamine was even demonstrated to increase cardiac output markedly while SVR fell in septic patients without shock.³⁰ Conversely, in another study in patients with severe septic shock, cardiac output did not increase significantly with dopamine at doses up to 25 µg/kg/min while SVR either did not change or significantly increased.³¹ This emphasizes the great heterogeneity in the response to dopamine among septic patients and hence the difficulty to predict clinical hemodynamic effects from pharmacologic properties because of interindividual differences in terms of severity of the insult, underlying diseases, comorbidities, integrity of the neurovegetative status, drugs concomitantly prescribed, and other factors.

In patients with septic shock and depressed myocardial function, dobutamine is expected to increase stroke volume and heart rate owing to its β₁-adrenergic properties but a vasodilatory effect owing to its β₂-adrenergic properties. Accordingly, an increase in cardiac output and a decrease in SVR with dobutamine were reported in septic patients.^32,³³ This emphasizes the need to give a potent vasopressive agent to septic shock patients when dobutamine is administered to support cardiac function in the presence of depressed myocardial contractility. One potential advantage of dobutamine is the decrease in cardiac filling pressures that could allow an additional volume infusion to improve further cardiac output when necessary. A change from dopamine to dobutamine was shown to result in lower right and left ventricular filling pressures and an increase in right ventricular ejection fraction for the same pulmonary artery pressure and right ventricular end-diastolic volume suggesting that dobutamine can exert a more favorable effect on cardiac contractility than dopamine.³⁴ This has justified the recommendation to give dobutamine rather than dopamine when use of an inotropic drug is judged necessary in patients with severe sepsis or septic shock.¹⁷ However, because of the alteration of the β-adrenergic pathway in the septic heart, the effect on stroke volume and cardiac output of a β-agonist agent such as dobutamine may be attenuated in septic patients in comparison with nonseptic patients. In this regard, infusion of dobutamine at 5 µg/kg/min, a dose able to increase cardiac output substantially in patients with congestive heart failure,³⁵ has been reported to exert variable effects in the context of sepsis. For example, dobutamine at 5 µg/kg/min was reported to induce a substantial increase in cardiac output in some studies in patients with severe sepsis^32,³⁶ and to have no significant effect on cardiac output in some studies investigating patients with septic shock.³⁷^–⁴¹ It is likely that these differences in response to dobutamine were related to various individual factors, including differences in the vasopressor treatment coadministered, in the degree of myocardial depression and/or β-receptor down-regulation. In this regard, Silverman and associates showed that incremental doses of dobutamine (0, 5, 10 µg/kg/min) produced a dose-related increase in cardiac output in septic patients without shock but no positive effect on cardiac output in patients with septic shock, even for the highest dose.²³ Interestingly, they also found that post-β-adrenergic receptor signal transmission was impaired only in patients of the septic shock group and that impairment of β-adrenergic receptor responsiveness found in both groups was significantly more marked in the septic shock group.²³ These findings which allow the divergent results of numerous studies to be reconciled^32,³⁶^–⁴³ emphasize the unpredictability of the effects of β-agonist agents in patients with sepsis. It must be stressed that the absence of positive cardiac response to dobutamine seems a marker of poor outcome in septic shock patients.^14,^15,⁴⁰ Because dobutamine also has potentially harmful effects (e.g., myocardial ischemia, cardiac arrhythmias), monitoring its effects on cardiac output to check its efficacy is the minimum required. However, no high-level recommendation on which method of cardiac output monitoring (e.g., pulmonary artery catheter, transesophageal Doppler, pulse contour method) is the more appropriate in this setting is currently available.