New pharmacologic approaches for the perioperative treatment of ischemic cardiogenic shock

REVIEW ARTICLE Martin J. London, MD Section Editor

New Pharmacologic Approaches for the Perioperative Treatment of Ischemic Cardiogenic Shock Andreas Lehmann, MD, and Joachim Boldt, MD

T

HE MOST COMMON cause of death for patients with acute myocardial infarction reaching the hospital alive is cardiogenic shock.1 Cardiogenic shock complicates 7% to 10% of all cases of acute myocardial infarction.2 Its incidence has stabilized within the last 30 years.3 The onset of cardiogenic shock after acute myocardial infarction is associated with a dramatic decrease in the prognosis for patient survival. In a period from 1975 to 1997, 12% of the patients hospitalized for acute myocardial infarction who did not have cardiogenic shock died, whereas 72% of the patients with cardiogenic shock died.3 In the 1990s, the prognosis of cardiogenic shock slightly improved by the increasing use of acute revascularization strategies.1-12 The SHOCK-trial (SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK2) showed a significant improvement of survival after 6 months for patients with acute myocardial infarction complicated by cardiogenic shock undergoing acute revascularization instead of initial medical stabilization. In 302 patients, 6-month mortality was 50.3% in the revascularization group compared with 63.1% (p ⫽ 0.027) in the group receiving initial medical therapy.2 Revascularization was achieved by coronary angioplasty (PTCA) in 64% and by coronary artery bypass grafting (CABG) in 36% of these patients.2 There was no difference in the 30-day mortality in patients undergoing PTCA or CABG.2 Based on these data, it has been recommended to acutely revascularize a patient with cardiogenic shock complicating acute myocardial infarction.1-3 Cardiac anesthesiologists will be continuously challenged by the increasing number of these patients at an extremely elevated peri-interventional or perioperative risk. This review is focused on some new drugs that might be promising as adjunct therapy to revascularization in patients with cardiogenic shock undergoing emergency CABG.

Hemodynamic signs of cardiogenic shock are a decrease in cardiac index (⬍2.2 L/min/m2) and an increase in pulmonary capillary wedge pressure (⬎15-18 mmHg).2,15 It is important to emphasize that diagnosis of cardiogenic shock is confirmed only by clinical symptoms; hemodynamics are just additional information to support the diagnosis.2,15 HEMODYNAMIC CHANGES IN ISCHEMIC CARDIOGENIC SHOCK

DIAGNOSIS OF CARDIOGENIC SHOCK

Myocardial ischemia and/or infarction lead to myocardial systolic and diastolic dysfunction. Systolic dysfunction results in decreased cardiac output and stroke volume leading to hypotension and a reduced coronary perfusion pressure.1 To compensate for hypotension, sympathetic tone is increased, heart rate increases, and vasoconstriction occurs.14 Decreased diastolic function results in pulmonary congestion and/or pulmonary edema with resultant hypoxemia. Vasoconstriction, tachycardia, and hypoxemia result in a vicious circle further aggravating myocardial ischemia and low cardiac output1,2 (Fig 1). Three possible outcomes may occur in this situation: 1. First, aggravating cardiogenic shock is the final result of this vicious circle and more than 50% of the patients die despite intervention.1,2,14 2. Second, cardiac “preshock” occurs as a result of partial compensation.14,16 In these patients, cardiac output and blood pressure remain moderately depressed. Increased heart rate, increased filling pressures, and pulmonary congestion characterize hemodynamics. This concept has gained recent interest16 because these patients are at high risk to reestablish cardiogenic shock. However, if treated early and sufficiently, outcome will be improved in these patients. 3. Third, complete compensation may occur.14 Patients who survive cardiogenic shock have a rather good intermediate-term prognosis. One-year mortality of pa-

Diagnosis of cardiogenic shock is based on clinical symptoms and hemodynamic data (Table 1). The leading clinical symptoms of cardiogenic shock are hypotension and hypoperfusion.2,3,13-15 Cardiogenic shock is a continuing state of hypotension in the absence of hypovolemia or rhythmic disorder leading to hypoperfusion. Systolic blood pressure is ⬍90 mmHg for more than 30 minutes or drug and/or mechanical support is needed to maintain a systolic blood pressure ⬎90 mmHg.2,13-15 Clinical signs of hypoperfusion are cold extremities, altered mental state, cyanosis, oliguria (⬍30 mL/h), and congestive heart failure.2,3,13-15

From the Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany. Address reprint requests to Andreas Lehmann, MD, Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany. © 2005 Elsevier Inc. All rights reserved. 1053-0770/05/1901-0020$30.00/0 doi:10.1053/j.jvca.2004.11.020 Key words: cardiogenic shock, heart surgery, levosimendan, LNAME

Journal of Cardiothoracic and Vascular Anesthesia, Vol 19, No 1 (February), 2005: pp 97-108

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LEHMANN AND BOLDT

Table 1. Diagnosis of Cardiogenic Shock Hochman et

al2

APsys ⬍90 mmHg or support to ⬎90 mmHg HR ⱖ60/min Oliguria ⬍30 mL/h Cold extremities

Goldberg et

al3

APsys ⬍80 mmHg absence of hypovolemia Oliguria Cold extremities Cyanosis Change in mental status Congestive heart failure

Killip and Kimball13

Ducas et al14

APsys ⬍90 mmHg

APsys ⬍90 mmHg or support to ⬎90 mmHg

APsys ⬍90 mmHg

Oliguria Cold extremities Cyanosis

Oliguria ⬍30 mL/h Cold extremities Cyanosis Change in mental status

Oliguria Cold extremities Cyanosis Change in mental status

CI ⬍2.2 L/min/m2 PCWP ⬎15 mmHg

Adams et al15

CI ⬍2.2 L/min/m2 PCWP ⬎18 mmHg

NOTE. Diagnosis of cardiogenic shock according to different authors. Cardiogenic shock is primarily diagnosed by clinical signs. The leading clinical symptoms are hypotension and hypoperfusion. Only 2 authors refer to hemodynamic data as additional information for the diagnosis of cardiogenic shock. Abbreviations: APsys, systolic blood pressure; HR, heart rate; CI, cardiac index; PCWP, pulmonary capillary wedge pressure.

tients alive after 30 days is 15%.17 More than 80% of the 1-year survivors of cardiogenic shock are in New York Heart Association class I or II.18 However, at 6 years, total cumulative mortality is more than 80%.19

role.28,29 Brunner et al30 proposed that the negative inotropic effect of high levels of NO is primarily caused by a reduction in myofilament responsiveness to calcium. This concept of cardiogenic shock resulting in SIRS offers some new therapeutic approaches.

ETIOLOGY OF CARDIOGENIC SHOCK

Acute aggravation of coronary artery disease is the cause of ischemic cardiogenic shock. Typically, cardiogenic shock results from massive damage to the left ventricular myocardium.1,16,20 At least 40% of the left ventricular myocardium is usually damaged in autopsy specimens.21 In the SHOCK trial registry, predominant left ventricular failure (78.5%) was the most common cause for cardiogenic shock.20 Isolated right ventricular failure was seen in only 2.8% of the patients. Mechanical complications of myocardial infarction accounted for 12% of all cardiogenic shock seen.20 Severe mitral regurgitation was seen in 6.9%, ventricular septal rupture in 3.9%, and cardiac tamponade in 1.4%. Confirmation of the specific etiology of ischemic cardiogenic shock has obvious importance for adequate therapeutic strategy.16 CARDIOGENIC SHOCK AND SYSTEMIC INFLAMMATORY RESPONSE SYNDROME

Recently, Hochman et al1 stated that cardiogenic shock results in a systemic inflammatory response syndrome (SIRS). After large myocardial infarctions, patients often show elevation of body temperature, white blood cell count, complement, interleukins, C-reactive protein, and other inflammatory markers.1 In patients with SIRS, inflammatory mediators activate inducible nitric oxide synthase resulting in increased levels of nitric oxide (NO).22 NO has a biphasic effect on the myocardium (Fig 2).23 Low levels of NO are cardioprotective24 and exert beneficial effects on local myocardial contractility and relaxation,25 whereas high levels of NO decrease myocardial contractility,26 suppress mitochondrial respiration in nonischemic myocardium,1 inhibit the positive inotropic response to ␤-adrenergic stimulation,27 and induce systemic vasodilation.1 The detrimental effects of high levels of NO on the ischemic myocardium are still not completely understood. Uncoupling of myocardial calcium metabolism might play an important

PRIMARY THERAPY FOR ISCHEMIC CARDIOGENIC SHOCK

In ischemic cardiogenic shock, early and sufficient revascularization is of utmost importance to improve survival.2,3,31 Restoration of coronary blood flow was the major predictor of survival in the SHOCK trial.32 Cardiac tamponade, ventricular septal rupture, and severe mitral regurgitation indicated immediate surgery.20,32 Interestingly, ventricular septal rupture was associated with a significantly higher mortality (87.5%) than all other categories.20 In the GUSTO-I trial (Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries31), the mortality rate was 32% for patients with cardiogenic shock in whom successful revascularization was achieved by PTCA. In those patients undergoing CABG, mortality was 29%.31 In patients with lytic therapy alone, the mortality rate was 75%.31 In the SHOCK trial,2 the only prospective and randomized study in patients with cardiogenic shock, patients undergoing revascularization had a significantly better survival (50.3%) at 6 months compared with initial medical stabilization (63.1%). PTCA accounted for 64% of the first attempt of revascularization and surgery (CABG) for 36%; mortality at 30 days did not differ between the 2 revascularization strategies.2 Based on these data, early revascularization is strongly recommended by the American College of Cardiology and the American Heart Association guidelines as a class IA indication for patients aged ⬍75 years with cardiogenic shock within 36 hours of an acute ST-elevation myocardial infarction.33

INTRA-AORTIC BALLOON COUNTERPULSATION IN ISCHEMIC CARDIOGENIC SHOCK

Intra-aortic balloon counterpulsation (IABP) is widely used in patients experiencing hemodynamic instability caused by myocardial infarction and/or cardiogenic shock.34,35 IABP increases coronary perfusion during dias-

NEW DRUGS FOR CARDIOGENIC SHOCK

99

Fig 1. The vicious circle of self-aggravating myocardial ischemia and/or infarction leading to cardiogenic shock is presented. Myocardial ischemia leads to myocardial systolic and diastolic dysfunction. Systolic dysfunction results in hypotension and hypoperfusion. Decreased diastolic function results in pulmonary congestion and/or pulmonary edema. Finally, reduced coronary perfusion pressure, vasoconstriction, tachycardia, and hypoxemia further aggravate ischemia and cardiogenic shock may develop.

tole by augmentation of diastolic blood pressure.14 By systolic deflation of the balloon, it decreases cardiac afterload, decreases myocardial oxygen consumption, and increases cardiac output.14 In the SHOCK trial registry,2 an IABP was implanted in 86% of the patients studied. Although there is no doubt about the physiological advantages of an IABP implantation in patients with cardiogenic shock, the beneficial effect on outcome is still questionable.36 In patients with ischemic cardiogenic shock undergoing thrombolytic therapy, use of IABP was associated with a significant reduction in mortality rates.37 However, IABP had no effect on mortality in patients undergoing PTCA.38 In patients undergoing revascularization either by CABG or PTCA, it is difficult to separate out the effects of IABP on survival.16 IABP is usually combined with revascularization in these patients. There is no doubt, IABP can help stabilize some patients and may make revascularization safer.16,38

PHARMACOTHERAPY FOR ISCHEMIC CARDIOGENIC SHOCK

All drugs given for the treatment of cardiogenic shock relieve symptoms, but they cannot treat the cause of ischemic cardiogenic shock. The goal of any pharmacologic therapy in cardiogenic shock is to restore nutritional blood flow and prevent further damage of vital organs. Catecholamines Adjunct pharmacologic therapy of cardiogenic shock is usually based on catecholamines and/or phosphodiesterase (PDE) inhibitors.2,3,15,16,22,39,40 The hemodynamic effects of catecholamines used for cardiogenic shock are listed in Table 2. All catecholamines act by membrane-bound adrenoreceptors39 mediated by G protein and cyclic adenosine monophosphate

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Fig 2. The biphasic effects of nitric oxide (NO) on the myocardium and peripheral vessels. Although low levels of NO exert positive effects on the myocardium, excessive levels of NO might be detrimental to cardiocirculatory function.

(cAMP) as the second messenger. The currently available catecholamines finally cause an increase of intracellular calcium in the cardiac myocytes.41 The overload with intracellular cal-

cium leads to calcium-induced arrhythmias and increases the metabolic demands of the myocytes.42 Increasing contractility and cardiac output by catecholamines in an ischemic myocar-

Table 2. Hemodynamic Effects of Catecholamines and Phosphodiesterase Inhibitors Drug

CO

dp/dt

HR

SVR

PVR

PCWP

MVO2

Dobutamine 2-12 ␮g/kg/min Dopamine 0-3 ␮g/kg/min 3-8 ␮g/kg/min ⬎8 ␮g/kg/min Dopexamine 0.5-6 ␮g/kg/min Epinephrine 0.01-0.4 ␮g/kg/min Norepinephrine 0.01-0.3 ␮g/kg/min PDE inhibitors

***

*

**

+

+

+ or N

*

* ** ** **

* * * *

* * * (+) *

+ + * ++

+ + N (*) +

* * * or N +

* * ** (*)

**

*

**

* (+)

(*)

* or N

**

*

*

N (*+)

**

N

N

*

**

*

*

++

+

++

+

NOTE. PDE inhibitors are usually given as a loading dose followed by a continuous infusion: Amrinone: 0.5-1.5 mg/kg loading dose, 10-30 ␮g/kg/min continuous infusion; Milrinone: 50 ␮g/kg loading dose, 0.375-0.75 ␮g/kg/min continuous infusion; Enoximone: 0.5-1.0 mg/kg loading dose, 2.5-20 ␮g/kg/min continuous infusion. The indicated doses represent the most common dose ranges. For the individual patient, a deviation from these recommended dose might be indicated. Abbreviations: CO, cardiac output; dp/dt, myocardial contractility; HR, heart rate; SVR, systemic vascular resistance; PVR, pulmonary vascular resistance; PCWP, pulmonary capillary wedge pressure; MVO2, myocardial oxygen consumption; PDE inhibitors, phosphodiesterase inhibitors.

NEW DRUGS FOR CARDIOGENIC SHOCK

dium may aggravate ischemia and may increase the incidence of fatal arrhythmia. In addition, cardiac apoptosis may be increased by high blood concentrations of catecholamines like norepinephrine, leading to a further decrease of cardiac function.43 Treatment with adrenergic drugs leads to a desensitization of the myocytes for adrenergic stimulation. Uncoupling from G protein,44 sequestration,39 and downregulation of the receptors45 are the mechanisms to adapt and protect the myocytes from chronic intrinsic or extrinsic adrenergic stimulation. Within a few hours, this desensitization for adrenergic stimulation might reach clinical significance.46 In humans undergoing cardiac surgery with cardiopulmonary bypass, a decreased myocardial adenylyl cyclase response to ␤-adrenergic agonists was proven, regardless of whether long-term preoperative ␤-adrenergic antagonists were administered.47 In patients pretreated with ␤-blockers, the effects of ␤-adrenergic stimulation with catecholamines are difficult to predict. In ␤-blocked patients, dobutamine might not produce much increase in cardiac output.48 However, chronic treatment with ␤-blockers leads to an upregulation of ␤-adrenergic receptors, thus improving the inotropic response to adrenergic stimulation.49 No data exist on improving outcome of patients with cardiogenic shock treated by any catecholamine. Neither the European40 nor the US51 guidelines recommend the prolonged use of catecholamines for treatment of chronic heart failure. The value of dobutamine for treating acute worsening of heart failure has been insufficiently documented in controlled trials and its effects on prognosis remain unclear.50 PDE Inhibitors PDE inhibitors were introduced in the 1980s for the treatment of cardiac failure. They act by blocking PDE III, catalyzing the degradation of cAMP.39 In contrast to the catecholamines, the PDE inhibitors are independent from specific receptors at the surface of the myocyte.39,48 Both catecholamines and PDE inhibitors increase the second messenger cAMP. Increased cAMP increases intracellular calcium of the myocyte, leading to increased contractility by an increased number of actin-myosin crossbridges52 (Fig 3). Increased metabolic demands and increased incidence of arrhythmia are the undesired side effects of the intracellular overload with calcium.42,53 In vascular smooth muscle cells, increased levels of cAMP cause relaxation and vasodilation. The PDE inhibitors act as inodilating drugs.39,54 Treatment with PDE inhibitors may be associated with thrombopenia.39 Chronic treatment with milrinone for heart failure has increased mortality55 and is discouraged.50,51 In a recent metaanalysis on the effectiveness of catecholamines and PDE inhibitors, 21 trials including 632 patients were reviewed.56 The authors concluded that such treatment provides little evidence of improved symptoms or patient outcomes and may not be safe.56 Five smaller noncontrolled studies in patients treated with PDE inhibitors for cardiogenic shock were published.57-61 Mostly, patients undergoing cardiac surgery with CPB were included. An improvement in hemodynamics was seen in all 5 studies; mortality ranged from 20% to 62% (Table 3).

101

Emerging Drugs for the Treatment of Heart Failure and Cardiogenic Shock Various drugs are under current consideration for the treatment of decompensated heart failure and cardiogenic shock62 (Table 4). These approaches include designed drugs from various classes and a recombinant human cardiac neurohormone, and, most interestingly, these approaches are based on rather different concepts of pathophysiology. Research is focused on 2 positive inotropic drugs, toborinone (PDE inhibitor) and levosimendan (calcium sensitizer); 2 vasodilating drugs, tezosentan (endothelin antagonist) and nesiritide (natriuretic peptide); and a strong vasoconstrictor, L-NAME (NG-Nitro-LArginine-Methyl Ester, inhibitor of nitric oxide synthase). Positive Inotropic Drugs Toborinone. The positive inotropic effects of toborinone are produced by inhibition of phosphodieseterase III with a resulting increase in cAMP and intracellular calcium.63 Toborinone is a potent balanced venous and arterial vasodilator.63,64 However, unlike most PDE III inhibitors and ␤-receptor agonists, toborinone does not induce a significant rise in heart rate.63,65 This latter effect is thought to be caused by simultaneous electrophysiological effects, specifically inhibition of potassium inward and delayed rectifier currents.65 These electrophysiological effects result in a prolongation of the action potential.63 In patients with stable congestive heart failure, toborinone did not increase myocardial oxygen consumption despite its positive inotropic effect.66 In experimental ischemia, toborinone improved myocardial energetics in comparison to amrinone.67 These effects were attributed to a smaller rise in heart rate and an increase in coronary blood flow in the ischemic region.67 In 12 patients undergoing cardiac surgery for valvular disease, toborinone improved hemodynamics when cardiac index was ⬍2.8 L/min/m2 or pulmonary capillary wedge pressure (PCWP) was ⬎8 mmHg.68 In experimental ventricular tachycardia, toborinone aggravated halothane-epinephrine–induced arrhythmia to ventricular fibrillation.69 Safety data in larger clinical trials, especially regarding arrhythmia, are not yet published.56,63 No data on toborinone in human ischemic heart failure or cardiogenic shock have been published. Levosimendan. Levosimendan is a new positive inotropic drug, belonging to the class of calcium sensitizers. The concept of calcium sensitization hypothesizes that myocardial contractility is increased by drugs directly interacting with contractile proteins.42,70 Levosimendan stabilizes the calcium-induced conformational change of cardiac troponin C (cTnC) only during systole by binding to the calcium-saturated conformation of cTnC.42,71,72 In contrast to other positive inotropic drugs, levosimendan does not increase intracellular calcium.42,52 Therefore, levosimendan exerts its positive inotropic effects by prolonging the effective cross-bridging time52 (Fig 3). It does not increase the number of actin-myosin crossbridges. Positive inotropy with normal levels of intracellular calcium avoids the undesired side effects of increased intracellular calcium like an increased oxygen consumption73,74 and an increased risk for fatal arrhythmia.53,75 In vitro levosimendan is a highly selective inhibitor of phophodiesterase III, however, at concentrations

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Fig 3. Mechanism of action of positive inotropic drugs and energetic demands. Myocardial contraction is based on the interaction of actin and myosin during systole. During diastole, cross-bridging of actin and myosin is blocked by troponin-tropomyosin-complex. By increasing intracellular calcium during systole, calcium binds to troponin C resulting in a conformational change of troponin-tropomyosin complex. The conformational change of troponin-tropomyosin complex allows cross-bridging of actin and myosin; contraction starts. The energetic demand for one cross-bridge of actin and myosin is one molecule of ATP. Above, the untreated situation in the myocardium is shown resulting in a normal cross-bridging time of actin and myosin and normal energy consumption. In the middle, levosimendan stabilizes the calcium-induced conformational change of troponin C during systole, resulting in an increase of cross-bridging time. The increased cross-bridging time increases contractility. The number of cross-bridges is not increased. The energetic demands remain unchanged by levosimendan. Intracellular calcium load is not augmented. Below, catecholamines and PDE III inhibitors raise intracellular calcium concentration during systole, resulting in an increased number of cross-bridges during systole. The increased number of cross-bridges results in an increased contractility. The energetic demands are increased by the additional number of cross-bridges and by the increased work of calcium-pumps and the end of systole. (Reprinted with permission.52)

exceeding the pharmacologically relevant concentrations for inducing positive inotropic effects.76 In contrast to the PDE inhibitors, the positive inotropic effects of levosimendan are not antagonized by inhibition of the cAMP-dependent protein kinase.77 The calcium-dependent binding of levosimendan to cTnC has no influence on the affinity of calcium to cTnC. This results in minimal effects on diastole.42 Levosimendan was found to preserve diastolic function.78 Uncoupling of myocardium calcium metabolism might play an important role in the detrimental effects on ischemic myocardium mediated by excessive NO levels.30 Levosimendan activates adenosine triphosphate (ATP)-sen-

sitive potassium channels (KATP-channels) in vascular smooth muscle cells,79 cardiac myocytes,80 and mitochondria.81 Therefore, levosimendan has vasodilating effects79,82 and anti-ischemic properties53,83 by opening KATP-channels. Opening KATPchannels is an obligatory step of ischemic and pharmacological preconditioning of the human myocardium.84,85 Activators of the KATP-channels, like nicorandil, have proven beneficial effects in patients with unstable angina.86 At doses simultaneously increasing myocardial contractility, levosimendan reduced experimental infarct size.83 It increased survival rate and the number of rats without any arrhythmia in regional myocardial ischemia.75 Levosimendan was also found to enhance

NEW DRUGS FOR CARDIOGENIC SHOCK

103

Table 3. Phosphodiesterase Inhibitors for the Treatment of Cardiogenic Shock Author

Drug

Patients

Control

N

Mortality

CI

PCWP

Goenen57 Iversen58 Vincent59 Vincent60 Kochi61

Amrinone Enoximone Enoximone Enoximone Milrinone

Post-CPB Post-CPB CF/post-CPB CF/post-CPB Post-CPB

No No No No No

5 13 18 13 26

1 6 ? 8 25%

* * * * N

+ + + + N

Abbreviations: N, number of patients; CI, cardiac index; PCWP, pulmonary capillary wedge pressure; post-CPB, patient undergoing cardiac surgery with cardiopulmonary bypass; CF, cardiac failure.

contractile function of stunned myocardium in patients with acute coronary syndrome.87 Based on its positive inotropic and anti-ischemic effects, levosimendan was proposed for patients with myocardial ischemia simultaneously requiring inotropic support. Levosimendan is recommended by the guidelines of the European Society of Cardiology50 for acute worsening of heart failure88 and for acute heart failure after myocardial infarction.89 This recommendation is based on 2 studies in humans.88,89 Two noncontrolled studies of levosimendan as add-on drug to catecholamine therapy in patients with cardiogenic shock were published (Table 5). In 10 patients with cardiogenic shock of surgical (n ⫽ 2) and nonsurgical origin (n ⫽ 8), levosimendan improved hemodynamics by increasing cardiac index and decreasing systemic vascular resistance.90 Two of these patients died within 36 hours, 4 patients died later in the hospital, and 4 patients were discharged home. In another series of 10 patients with ischemic cardiogenic shock undergoing cardiac surgery, levosimendan also increased cardiac index and decreased systemic vascular resistance.91 Two patients died and 8 patients were discharged home or retransferred to the admitting hospital. No controlled study for the use of levosimendan in patients with cardiogenic shock has yet been published. In ischemic heart failure, levosimendan might be of great advantage as an inoprotective drug. However, this hypothesis needs to be confirmed by future studies. Vasodilating Drugs Tezosentan. Endothelin (ET)-1 is a powerful mediator of vasoconstriction, and it is increased in patients with heart failure.92 The height of the ET-1 plasma concentration is correlated with the severity of the disease.92 Two receptors for

ET-1 are known: ETA and ETB.93 ETA receptors are located in smooth muscle cells mediating vasoconstriction, vasomotion, and proliferation.94 ETB receptors are found in the brain, endothelium, and some smooth muscle cells.92 They mediate endothelium-dependent vascular smooth muscle relaxation.95 In the failing human heart, density of ET receptors is upregulated, mainly because of an upregulation of ETA subtype.96 This upregulation is more pronounced in ischemic heart failure compared to dilated cardiomyopathy.97 Increased ET receptor activity and increased endogenous ET-1 seem to contribute to the increased vascular tone and to the progression of atherosclerotic disease in ischemic heart failure.98 Inhibition of endothelin function was associated with improved hemodynamics, blunted vascular hypertrophy, and cardiac remodeling.92,99 Tezosentan is a specific and potent dual ET-receptor antagonist, binding to ETA and ETB receptors.92 It has a rapid onset92 and a rather short biphasic elimination half-life (elimination half-life 6 minutes, distribution half-life 3 hours).100 Tezosentan improved cardiac index by reductions in PCWP and pulmonary and systemic vascular resistance.92 In contrast to other vasodilators, tezosentan seems to improve cardiac performance.101 In the Randomized Intravenous TeZosentan study (RITZ-2), tezosentan was shown to improve hemodynamics in patients with acute decompensated heart failure.102 In patients with acute heart failure and acute coronary syndrome, treatment with tezosentan was compared with placebo (RITZ-4103). Therapy with tezosentan did not reduce the rate of death and did not reduce worsening of heart failure, recurrent ischemia, or new myocardial infarction. In the RITZ-5 study,104 tezosentan was tested in patients with pulmonary edema. Again, tezosentan did not improve the treatment of pulmonary edema and the out-

Table 4. Emerging Drugs for Heart Failure and Cardiogenic Shock Drug

CO

PCWP

AP

HR

Arrhyth.

Onset

Offset

Diur.

Shock

Toborinone L-simendan Tezosentan Nesiritide L-NAME

*** ** ** * +

++ + + ++ **

* or + + + + ***

N * N N (+)

*** N N N ?

Short Short Short Short Short

Moderate Very long Short Long Moderate

N N N ** *

No Yes No No Yes

NOTE. Positive inotropic drugs: Toborinone: phosphodiesterase inhibitor. L-simendan: levosimendan, calcium sensitizer. Vasodilating drugs: Tezosentan: endothelin antagonist. Nesiritide: natriuretic peptide. Vasoconstricting drug: L-NAME: NG-Nitro-L-Arginine-Methyl Ester, inhibitor of nitric oxide synthase. Abbreviations: CO, cardiac output; PCWP, pulmonary capillary wedge pressure; AP, arterial pressure; HR, heart rate; arrhyth, arrhythmogenic potential; diur, diuresis; shock cardiogenic shock; no, not yet used in patients with cardiogenic shock; yes, already used in patients with cardiogenic shock. Modified from Young.62

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LEHMANN AND BOLDT

Table 5. Levosimendan for the Treatment of Cardiogenic Shock Author

Patients

Control

N

Mortality

CI

SVR

PCWP

Delle Karth90 Lehmann91

CF/post-CPB Post-CPB

No No

10 10

6 2

* *

++ ++

+ +

Abbreviations: N, number of patients; CI, cardiac index; SVR, systemic vascular resistance; PCWP, pulmonary capillary wedge pressure; post-CPB, patient undergoing cardiac surgery with cardiopulmonary bypass; CF, cardiac failure.

come of the patients compared with placebo.104 Tezosentan was not used for the treatment of cardiogenic shock. Nesiritide. Nesiritide is a recombinant human brain-type natriuretic peptide (BNP) with vasodilatory, diuretic, natriuretic, and neurohormonal effects.105 Nesiritide is structurally and biochemically identical to endogenously produced BNP, an oligopeptide with 32 amino acid residues.105 In humans, BNP has a key role to maintain hemodynamic and neurohumoral equilibrium.106 In response to volume overload, BNP is predominantly secreted by cardiac ventricles107 to regulate intravascular volume and pressure.105,106 The vasodilatory, diuretic, and natriuretic effects of BNP are mediated by interaction with natriuretic peptide receptor A and to a lesser extent with natriuretic peptide receptor B. These receptors are placed on vascular smooth muscle cells, endothelial cells, kidneys, and adrenal gland.105,108 In patients with heart failure, intravenous nesiritide acts as a vasodilator and reduces preload.109,110 It significantly reduces PCWP and right atrial pressure. Additionally, systemic vascular resistance is decreased and subsequently cardiac index is increased.105 Nesiritide itself has no positive inotropic effects as shown in isolated dog atrial and ventricular preparations.111 Mean arterial pressure tends to be reduced; however, this drop in arterial pressure is not associated with reflex tachycardia.110 There is no evidence for tachyphylaxis of these hemodynamic effects.105,109 Nesiritide has significant diuretic and natriuretic effects in patients with congestive heart failure and in healthy volunteers.105,112 Long-term treatment with nesiritide seems to result in a decreased level of endogenous BNP, corresponding to symptomatic improvement of congestive heart failure.105 Nesiritide appears to reduce plasma aldosterone110 and plasma renin activity,112 and plasma norepinephrine levels were significantly reduced in patients with congestive heart failure.113 Interestingly, treatment with nesiritide mimics a natural compensatory mechanism in patients with congestive heart failure. In these patients, plasma BNP levels are significantly increased and correspond to the degree of the disease.114-116 Nesiritide was used in 4 prospective, randomized, multicenter trials, including more than 1,100 patients hospitalized for decompensated cardiac failure109,110,117 (2 studies were reported in 1 publication). In the Vasodilation in the Management

of Acute Cardiac failure (VMAC) study,109 nesiritide was compared with nitroglycerin and placebo. Nesiritide rapidly and persistently decreased PCWP throughout 48 hours. The reductions of PCWP were more pronounced with nesiritide compared with nitroglycerin. There was no difference in the relief of dyspnea or mortality at 6 months between nesiritide or nitroglycerin.109 In a subgroup analysis of the VMAC study, nesiritide was as safe as nitroglycerin in heart failure patients with acute coronary syndrome.118 Colucci et al110 compared nesiritide with placebo. Nesiritide improved hemodynamics and clinical status in decompensated congestive heart failure. When compared with dobutamine (Prospective Randomized Evaluation of Cardiac Ectopy with DobutaminE or Natrecor Therapy [PRECEDENT]117), nesiritide reduced ventricular ectopy, whereas dobutamine had a significant proarrhythmic and chronotropic effect. Nesiritide is indicated in congestive heart failure with volume overload and dyspnea at rest.105,119 Major contraindications for the use of nesiritide are hypotension and cardiogenic shock.105,119 To the authors’ knowledge, no data on nesiritide in cardiogenic shock were published. Nesiritide is not recommended by the actual European50 or US51 guidelines for the treatment of cardiac failure. Vasoconstricting Drugs L-NAME. A completely different approach to improve outcome in patients with cardiogenic shock is based on the work of Cotter and colleagues.27,120 They hypothesized an excess of nitric oxide as one of the most important factors in the genesis and the progression of cardiogenic shock. They propose that cardiogenic shock is no longer just a critical loss of cardiac pump function. Cotter et al27 used L-NMMA (N-monomethyl L-arginine) and L-NAME (N-Nitro L-arginine methylester)120 as add-on therapy to catecholamines (Table 6). Both drugs are equipotent inhibitors of NO production from arginine. L-NAME is used in various experimental models to induce hypertension.121,122 In a noncontrolled pilot study,27 11 patients with cardiogenic shock persisting for more than 24 hours despite percutaneous revascularization, IABP, catecholamines, and mechanical ventilation were included. All were treated with L-NMMA for 5 hours in

Table 6. L-NAME for the Treatment of Cardiogenic Shock Author

Patients

Control

N

Mortality

CI

SVR

PCWP

Cotter27

Ischemic CF Ischemic CF

No Yes

11 2 ⫻ 15

4 27% L-NAME 67% control

+ +

*** ***

* ?

Cotter120

Abbreviations: N, number of patients; CI, cardiac index; SVR, systemic vascular resistance; PCWP, pulmonary capillary wedge pressure; ischemic CF, cardiac failure after acute myocardial infarction.

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addition to catecholamines. Within 10 minutes of L-NMMA administration, there were sharp increases of mean arterial pressure and systemic vascular resistance. Cardiac index further decreased from 2.0 ⫾ 0.5 to 1.7 ⫾ 0.4L/min/m2. Within 24 hours cardiac index returned to pretreatment level. Urine output was significantly increased by L-NMMA. Ten of these 11 patients could be weaned off mechanical ventilation and IABP. Seven patients were alive after 1 month.27 In a prospective randomized trial, Cotter et al120 included 30 patients with acute coronary syndrome and cardiogenic shock. L-NAME was given for 5 hours as add-on therapy to percutaneous revascularization, IABP, mechanical ventilation, and catecholamines (dopamine and norepinephrine). Again, the administration of L-NAME resulted in sharp vasoconstriction. Mean arterial pressure and systemic vascular resistance were significantly increased, whereas cardiac index was decreased. Urine output was nearly doubled in the L-NAME group. After 1 month, survival was 73% in the L-NAME arm, while it was 33% in the control group. Cotter et al120 concluded that L-NAME may be a new, safe, efficacious approach for patients with cardiogenic shock. This is the only prospective, controlled, randomized study with an emerging drug for the treatment of cardiogenic shock. The concept of Cotter and colleagues is supported by work from Lim et al.123 They found a mortality rate of 65% in 62 patients with cardiogenic shock. Twenty percent of these patients died from fatal arrhythmia, 35% died with low cardiac index (CI ⬍2.2 L/min/m2), whereas 45% (18 patients) died with a normalized cardiac index (CI ⬎2.2L/min/m2). Only 9 of these patients had evidence of infection. Lim et al123 concluded that several patients with cardiogenic shock die despite normalization of CI, suggesting a maldistributive effect with low systemic vascular resistance. Further support is given by the observation that cardiogenic shock results in SIRS.1 SIRS results in increased levels of NO.22 NO has a biphasic effect on the myocardium.23 Although low levels of NO are cardioprotective, excess levels of NO have further detrimental effects on the myocardium and vascular tone. Excessive NO decreases myocardial contractility,26 suppresses mitochondrial respiration in nonischemic myocardium,1 inhibits the positive inotropic response to ␤-adrenergic stimulation,27 and induces systemic vasodilation.1 Menon124 stated in an editorial that clinical presentation of ischemic cardiogenic shock in many patients re-

sembles a sepsis syndrome, with low-to-normal systemic vascular resistance and increased inflammatory cytokines. A larger confirmatory trial (SHOCK-2: SHould we inhibit nitric Oxide synthase in patients with Cardiogenic shocK?) is currently designed to test the promising role of NO synthase inhibition in patients with cardiogenic shock.1 CONCLUSION

Cardiogenic shock is the most common cause of death for patients with acute myocardial infarction reaching the hospital alive. Early revascularization is strongly recommended by the American College of Cardiology/American Heart Association guidelines as a class IA indication for patients aged ⬍75 years with cardiogenic shock within 36 hours of an acute ST-elevation myocardial infarction. Mortality for patients with cardiogenic shock undergoing either interventional or surgical revascularization does not differ. Implantation of an IABP is justified, although its beneficial effects on survival have not yet been proven. Several new drugs are under consideration for adjunct therapy for decompensated cardiac failure and/or cardiogenic shock. Toborinone is a new PDE inhibitor with no increase in heart rate and myocardial oxygen consumption. Tezosentan, an ET-receptor antagonist, and nesiritide, a recombinant human BNP, act as vasodilators reducing pre- and afterload. These 3 drugs have yet not been studied in human cardiogenic shock. Two new hypotheses of treating ischemic cardiogenic shock were published. First, levosimendan, a calcium sensitizer, simultaneously increases myocardial contractility and protects the heart from ischemia. These cardioprotective effects are caused by activation of KATP-channels in mitochondria. The concept of inoprotection is yet not proved in a prospective, randomized, and controlled trial. Second, L-NAME, an inhibitor of NO-synthase, acts as a strong vasocontrictor. The hypothesis postulates that cardiogenic shock is not only a failure of cardiac pump function. Cardiogenic shock is mainly caused by an excess of NO leading to myocardial depression and vasodilation. In this concept, cardiogenic shock masquerades as a sepsis syndrome. This concept is the only one of all the new ideas of treating cardiogenic shock that was proven in a small, prospective, controlled, and randomized trial. A larger clinical trial (SHOCK-2) is currently designed.

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