cardiogenic shock

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CARDIOGENIC SHOCK

Steven M. Hollenberg, MD

Cardiogenic shock is a state of inadequate tissue perfusion owing to cardiac dysfunction. The leading cause of cardiogenic shock is acute myocardial infarction.' Despite advances in management of heart failure and acute myocardial infarction, the mortality of patients with cardiogenic shock has remained high, with reported mortality rates ranging from 50% to 80%.23, 33 Recent data suggest an increase in survival in the 1990s, concident with the use of reperfusion ~trategies .~~ Cardiogenic shock, however, remains the most common cause of death in hospital- ized patients with acute myocardial infarction.

DEFINITION

Defined clinically, cardiogenic shock is decreased cardiac output and evidence of tissue hypoxia in the presence of adequate intravascular volume. The diagnosis of circulatory shock is made at the bedside by observing hypotension along with a combination of clinical signs indica- tive of poor tissue perfusion, including oliguria, clouded sensorium, and cool, mottled extremities. Cardiogenic shock is diagnosed after documentation of myocardial dysfunction and exclusion or correction of factors such as hypovolemia, hypoxia, and acidosis. Hemodynamic crite- ria include sustained hypotension (systolic blood pressure <90 mm Hg for at least 30 minutes) and a reduced cardiac index (<2.2 L/min/m2) in the presence of elevated pulmonary capillary occlusion pressure (>15 mm Hg).20

From the Sections of Cardiology and Critical Care Medicine, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois

CRITICAL CARE CLINICS

VOLUME 17 m B E R 2 * APRIL 2001 391

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EPIDEMIOLOGY AND ETIOLOGY

Accurate determination of the precise incidence of cardiogenic shock is difficult because patients who die before reaching the hospital are not given the diagnosis.23 Nonetheless, estimates from a variety of sources have indicated an incidence rate between 6% and 8%, and this rate has remained fairly stable from 1975 to 1997.23*24,40 The most common cause of cardiogenic shock is extensive acute myocardial infarction, although smaller infarctions in patients with previously compromised left ventricular function also may precipitate shock. Shock with a delayed onset may result from infarct extension, reocclusion of a previously patent infarct artery, or decompensation of myocardial function in the noninfarct zone because of metabolic abnormalities. Areas of nonfunctional but viable myocardium, stunned or hibernating, also can cause or contribute to the development of cardiogenic shock in patients after myocardial infarction.

Cardiogenic shock can be caused by mechanical complications, such as acute mitral regurgitation, rupture of the interventricular septum, rupture of the free wall, or by large right ventricular infarctions. Other causes of cardiogenic shock include myocarditis, end-stage cardiomyopathy, myocardial contusion, septic shock with severe myocardial depression, myocardial dysfunction after prolonged cardiopulmonary bypass, valvular heart disease, and hypertrophic obstructive cardiomyopathy (Table 1). In the largest registry of patients with cardiogenic shock, 74.5% of patients had predominant left ventricular failure, 8.3% had acute mitral regurgitation, 4.6% had ventricular septa1 rupture, 3.4% had iso- lated right ventricular shock, 1.7% had tamponade or cardiac rupture, and 8% had shock resulting from other causes.33

Some patients may have cardiogenic shock at initial presentation, but shock most often evolves over several hours.12 In the GUSTO trial4n 89% of patients with cardiogenic shock developed shock after admission. The median delay from onset of infarction to development of cardiogenic shock in the randomized SHOCK trial was 5.6 hoursM; the delay in the SHOCK trial registry was 7 hours.

Risk factors for the development of cardiogenic shock in patients with myocardial infarction include increasing age, diabetes, and a history of previous infar~tion.~~, 49 Decreased ejection fractions and larger infarctions (as evidenced by higher cardiac enzyme concentrations) are also predictors of the development of cardiogenic 49 Recent analysis from the GUSTO-3 trial has identified age, lower systolic blood pressure, heart rate, and Killip class as significant predictors of the risk for development of cardiogenic shock after presentation with acute myocardial infarcti~n.~~

Cardiogenic shock most often is associated with anterior myocardial infar~tion.~~ Angiography most often demonstrates multivessel coronary disease (in the SHOCK trial left main occlusion was found in 20% of patients, three-vessel disease in 649'0, two-vessel disease in 23%, and one-vessel disease in 13% of patients).34 This finding is important because

CARDIOGENIC SHOCK 393

Table 1. CAUSES OF CARDIOGENIC SHOCK

Acute Myocardial Infarction Pump failure

Large infarction Smaller infarction with pre-existing left ventricular dysfunction Infarct extension Infarct expansion Reinfarction

Acute mitral regurgitation owing to papillary muscle rupture Ventricular septa1 defect Free-wall rupture Pericardial tamponade

Right ventricular infarction

End-stage cardiomyopathy Myocarditis Myocardial contusion Prolonged cardiopulmonary bypass Septic shock with severe myocardial depression Left ventricular outflow tract obstruction

Mechanical complications

Other Conditions

Aortic stenosis Hypertrophic obstructive cardiomyopathy

Mitral stenosis Left atrial myxoma

Obstruction to left ventricular filling

Acute mitral regurgitation (chordal rupture) Acute aortic insufficiency

compensatory hyperkinesis normally develops in myocardial segments that are not involved in an acute myocardial infarction, which helps maintain cardiac output. Failure to develop such a response, because of previous infarction or high-grade coronary stenoses, is an important risk factor for cardiogenic shock and death.12

PATHOGENESIS

Systemic Effects

Cardiac dysfunction in patients with cardiogenic shock usually is initiated by myocardial infarction or ischemia. The myocardial dysfunction resulting from ischemia worsens ischemia, creating a downward spiral (Fig. 1). When a critical mass of left ventricular myocardium is ischemic or necrotic and fails to pump, stroke volume and cardiac output decrease. Myocardial perfusion, which depends on the duration of dias- tole and on the pressure gradient between the coronary arterial system and the left ventricle, is compromised by hypotension and tachycardia, exacerbating ischemia. The increased ventricular diastolic pressures caused by pump failure further reduce coronary perfusion pressure,

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I MYOCARDIAL DYSFUNCTION 1 I SYSTOLIC// DIASTOLIC I

4 Systemic Hypotension perfusion I

fluid retention

MYOCARDIAL DYSFUNCTION

Figure 1. The downward spiral in cardiogenic shock. LVEDP = Left ventricular end- diastolic pressure.

and the additional wall stress elevates myocardial oxygen requirements, further worsening ischemia. Decreased cardiac output also compromises systemic perfusion, which can lead to lactic acidosis and further compromise of systolic performance.

Compensatory mechanisms activated when myocardial function is depressed include sympathetic stimulation to increase heart rate and contractility and renal fluid retention to increase preload. These compensatory mechanisms may become maladaptive and actually can worsen the situation when cardiogenic shock develops. Increased heart rate and contractility increase myocardial oxygen demand and exacerbate ischemia. Fluid retention and impaired diastolic filling caused by tachycardia and ischemia may result in pulmonary congestion and hypoxia. Vasoconstriction to maintain blood pressure increases myocardial afterload, further impairing cardiac performance and increasing myocardial oxygen demand. This increased demand, in the face of inadequate perfusion, worsens ischemia and begins a vicious circle that will end in death if uninterrupted (Fig. 1).

One important consequence of this downward spiral in which ischemia worsens myocardial performance is that early intervention to relieve ischemia can reduce the incidence of cardiogenic shock. The fact that


most cases of cardiogenic shock occur after hospital admission emphasizes the importance of initiating of therapy for myocardial infarction, including aspirin, nitrates, beta blockers, and reperfusion therapy, as outlined in the American Hospital Association/ American College of Cardiology as soon as possible after presentation. Another important consequence is that aggressive supportive care is needed to maintain blood pressure and coronary perfusion. In addition, prompt initiation of reperfusion therapy is crucial once cardiogenic shock has en- sued.

Myocardial and Cellular Pathology

Progressive myocardial necrosis has been observed consistently in clinical and pathologic studies of patients with cardiogenic shock.12 Patients who develop shock after admission often have evidence of infarct extension, which can result from reocclusion of a transiently patent infarct artery, propagation of intracoronary thrombus, or a combination of decreased coronary perfusion pressure and increased myocardial oxygen demand.30* 49 Myocytes at the border zone of an infarction are more susceptible to additional ischemic episodes; therefore, these adjacent segments are at particular risk.53 Mechanical infarct expansion, which is seen most dramatically after extensive anterior myocardial infarction, also can contribute to late development of cardiogenic

Ischemia remote from the infarct zone may be particularly important in producing systolic dysfunction in patients with cardiogenic Patients with cardiogenic shock usually have multivessel coronary artery diseasel2, 33 with limited vasodilator reserve, impaired autoregulation, and consequent pressure-dependent coronary flow in several perfusion territories. Hypotension and metabolic derangements thus have the potential to impair the contractility of noninfarcted myocardium in patients with This impaired contractility can limit the compensatory hyperkinesis of uninvolved segments typically seen early after myocardial infar~t ion.~~

Myocardial diastolic function also is impaired in patients with cardiogenic shock. Myocardial ischemia causes decreased compliance, increasing the left ventricular filling pressure at a given end-diastolic volume.37 Compensatory increases in left ventricular volumes to maintain stroke volume further increase filling pressures. Elevation of left ventricular pressures can lead to pulmonary edema and hypoxemia.

Tissue hypoperfusion and consequent cellular hypoxia lead to an- aerobic glycolysis, with depletion of ATP, accumulation of lactic acid, and intracellular acidosis. Failure of energy-dependent ion transport pumps decreases transmembrane potential, causing intracellular accumulation of sodium and calcium and myocyte swelling.39 Cellular ischemia and intracellular calcium accumulation can activate intracellular pro tease^.^^ If the ischemia is severe and prolonged enough, myocardial cellular injury can become irre~ersible.~~

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Accumulating evidence indicates that apoptosis (programmed cell death) also may contribute to myocyte loss in myocardial infar~tion.~ Although necrosis clearly outweighs apoptosis in the core of an infarcted area, evidence for apoptosis has been found consistently in the border zone of infarcts after ischemia and reperfusion and sporadically in areas remote from the ischemic area.3 Activation of inflammatory cascades, oxidative stress, and stretching of myocytes have been proposed as mechanisms that activate the apoptotic pathways3 Although the magni- tude of apoptotic cell loss in myocardial infarction remains uncertain, inhibitors of apoptosis have been found to attenuate myocardial injury in animal models of postischemic reperfusion; these inhibitors also may have therapeutic potential for myocyte salvage after large infarction^.^

Reversible Myocardial Dysfunction

A key to understanding the pathophysiology and treatment of cardiogenic shock is to realize that large areas of nonfunctional but viable myocardium can cause or contribute to the development of cardiogenic shock in patients after myocardial infarction (Fig. 2). This reversible dysfunction can be described in two main categories: stunning and hibernation.

Myocardial stunning represents postischemic dysfunction that persists despite restoration of normal blood flow; eventually, however, myocardial performance recovers completely.* Direct evidence for myocardial stunning in humans recently has been found using positron

I Cell death 1

Ischemic Myocardium

\ Significant

Reperfusion residual

\ /stenosis

\ J \ / lnotropic Relief of support ischemia

I / myocardial function

Figure 2. After myocardial ischemia, necrosis or reversible dysfunction may occur. Myocar- dial stunning represents postischemic dysfunction that persists despite restoration of normal flow. These segments respond to inotropes and will recover function if supported. Hibernat- ing myocardium is a state of persistently impaired myocardial function at rest owing to residual stenosis; function can be restored to normal by relieving ischemia. Repetitive episodes of stunning can coexist with and/or mimic myocardial hibernation.


emission tomography (PET) scanning in patients with persistent wall motion abnormalities after angioplasty for acute coronary syndromes; perfusion measured by 13N-ammonia was normal in the presence of persistent contractile dysfunction.22 The pathogenesis of stunning has not been established conclusively but seems to involve a combination of oxidative stress, perturbation of calcium homeostasis, and decreased myofilament responsiveness to calcium, all in the setting of antecedent ischemia.8

Hibernating myocardium is in a state of persistently impaired function at rest caused by severely reduced coronary blood flow; inherent in the definition of hibernating myocardium is the notion that function can be returned to normal by improving blood Hibernation can be seen as an adaptive response to reduce contractile function of hypoper- fused myocardium and restore equilibrium between flow and function, thereby minimizing the potential for ischemia or necrosis.38 Revasculari- zation of hibernating myocardium can lead to improved myocardial function, and improved function seems to translate into improved prognosis.1°

Although hibernation is conceptually and pathophysiologically dif- ferent from myocardial stunning, the two conditions are difficult to distinguish in the clinical setting and may in fact coexist.8 Repetitive episodes of myocardial stunning can coexist with or mimic myocardial hibernation.8, 70 Consideration of myocardial stunning and hibernation is vital in patients with cardiogenic shock because of their therapeutic implications. Stunned and hibernating myocardium retain inotropic reserve and can respond to catecholamines.8 Function of hibernating myocardium can improve with revascularization, and function of stunned myocardium can improve with time. The notion that some myocardial tissue may recover function emphasizes the importance of measures to support hemodynamics and minimize myocardial necrosis in patients with shock.

CLINICAL ASSESSMENT AND INITIAL MANAGEMENT

Evaluation

The challenge in initial management of cardiogenic shock is that evaluation and therapy must begin simultaneously. The clinician must perform the clinical assessment required to understand the cause of shock while initiating supportive therapy before shock causes irrevers- ible damage. A practical approach is to make a rapid initial evaluation on the basis of a limited history, physical examination, and specific diagnostic procedures (Fig. 3). Cardiogenic shock is diagnosed after documentation of myocardial dysfunction and exclusion of alternative causes of hypotension such as hypovolemia, hemorrhage, sepsis, pulmonary embolism, tamponade, aortic dissection, and pre-existing valvular disease.

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Cardioaenic Shock

Initial Diaanostic Stem Directed history and physical exam EKG Echocardiography Laboratory Chest x-ray Pulmonary artery catheterization

\

Initial Manaaement Steps Supplemental oxygenlmechanical

ventilation Venous access EKG monitoring Pain relief Hernodynamic support

- Fluid challenge in patients with-

- Vasopressors for hypotension out pulmonary edema

unresponsive to fluids

Tissue Perfusion Adequate Perfusion Adequate Tissue Perfusion Remains Inadequate Without Conaestion With Pulmonarv Conaestion lnotropic IABP agents ~ 1 2 i l a t o r s Diuretics

Re perf usion Cath lab available / No cath lab available \ Cardiac catheterization Thrombolytic therapy & IABP

/ \ Angioplasty CABG Continued shock Clinical improvement

Figure 3. An approach to the diagnosis and treatment of cardiogenic shock caused by myocardial infarction. Right ventricular infarction and mechanical complications are dis- cussed in the text. CABG = Coronary artery bypass grafting; IABP = intra-aortic balloon pumping.

Patients with shock are usually ashen or cyanotic and can have cool skin and mottled extremities. Cerebral hypoperfusion may cloud the sensorium. Pulses are rapid and faint and may be irregular in the presence of arrhythmias. Jugular venous distention and pulmonary rales are usually present, although their absence does not exclude the diagnosis. A precordial heave resulting from left ventricular dyskinesis may be


palpable. The heart sounds may be distant, and third and/or fourth heart sounds are usually present. A systolic murmur of mitral regurgitation or ventricular septal defect may be heard, but these complications may occur without an audible murmur.

An electrocardiogram should be performed immediately. Other initial diagnostic tests should include a chest radiograph, complete blood count, and measurement of arterial blood gases, electrolytes, and cardiac enzymes.

Echocardiography is an excellent initial tool for confirming the diagnosis of cardiogenic shock and ruling out other causes of shock; therefore, early echocardiography should be routine. Echocardiography provides information on overall and regional systolic function and can reveal rapidly mechanical causes of shock such as papillary muscle rupture and acute mitral regurgitation, acute ventricular septal defect, and free wall rupture and t a m p ~ n a d e . ~ ~ Unsuspected severe mitral regurgitation is not uncommon. In some cases, echocardiography may reveal findings compatible with right ventricular infarction.

Invasive hemodynamic monitoring can be useful to exclude volume depletion, right ventricular infarction, and mechanical complications.12, 39

The hemodynamic profile of cardiogenic shock includes a pulmonary capillary occlusion pressure greater than 15 mm Hg and a cardiac index less than 2.2 L/min/m2.20 It should be recognized that optimal filling pressures may be greater than 15 mm Hg in individual patients because of left ventricular diastolic dysfunction. Right heart catheterization may reveal an oxygen step-up diagnostic of ventricular septal rupture or a large V wave that suggests severe mitral regurgitation. The hemodynamic profile of right ventricular infarction includes high right-sided filling pressures in the presence of normal or low occlusion pressures.46 Coronary angiography as part of a revascularization strategy considered farther on.

Initial Management

The initial approach to the patient in cardiogenic shock should include fluid resuscitation unless frank pulmonary edema is present. Central venous and arterial access, bladder catheterization, and pulse oximetry are routine. Oxygenation and airway protection are critical; intubation and mechanical ventilation often are required, if only to reduce the work of breathing and facilitate sedation and stabilization before cardiac catheterization. Electrolyte abnormalities should be corrected, because hypokalemia and hypomagnesemia predispose to ventricular arrhythmias. Relief of pain and anxiety with morphine sulfate (or fentanyl if systolic pressure is compromised) can reduce excessive sympathetic activity and decrease oxygen demand, preload, and afterload. Arrhythmias and heart block may have major effects on cardiac output and should be corrected promptly with antiarrhythmic drugs, cardioversion, or pacing. Measures that have been proved to

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improve outcome after myocardial infarction and are used routinely, such as nitrates, beta blockers, and angiotensin-converting enzyme inhibitors, have the potential to exacerbate hypotension in cardiogenic shock and should be stopped until the patient’s condition becomes stable.

In patients with inadequate tissue perfusion and adequate intravascular volume, cardiovascular support with inotropic agents should be initiated. Dobutamine, a selective P-adrenergic receptor agonist, can improve myocardial contractility and increase cardiac output, and it is the initial agent of choice in patients with systolic pressures greater than 80 mm Hg.37 Dobutamine may exacerbate hypotension in some patients and can precipitate tachyarrhythmias. Dopamine acts directly on myocardial P-adrenergic receptors and acts indirectly by releasing norepinephrine. It has inotropic and vasopressor effects, and its use is prefera- ble in the presence of systolic pressures less than 80 mm Hg.37, 50

Tachycardia and increased peripheral resistance with dopamine administration may exacerbate myocardial ischemia. In some situations, a combination of dopamine and dobutamine can be more effective than either agent When hypotension remains refractory, norepinephrine, a natural catecholamine with potent a- and P-adrenergic effects, may be necessary to maintain organ perfusion pressure.35

Catecholamine infusions need to be titrated carefully in patients with cardiogenic shock to maximize coronary perfusion pressure with the least possible increase in myocardial oxygen demand. Invasive hemodynamic monitoring can be extremely useful in allowing optimization of therapy in these unstable patients, because clinical estimates of filling pressure can be unreliable31; in addition, changes in myocardial performance and compliance and therapeutic interventions can change cardiac output and filling pressures precipitously. Optimization of filling pressures and serial measurements of cardiac output (and other parameters, such as mixed venous oxygen saturation) allow for titration of the dosage of inotropic agents and vasopressors to the minimum dosage required to achieve the chosen therapeutic goals. This minimizes the increases in myocardial oxygen demand and arrhythmogenic p ~ t e n t i a l . ~ ~

The phosphodiesterase inhibitors amrinone and milrinone have pos- itive inotropic and vasodilatory actions, with minimal chronotropic and arrhythmogenic effects compared with cat echo la mine^.^ Because they have long half-lives and the potential to cause hypotension and thrombo- cytopenia, however, they often are reserved for use when other agents have proved ineffective.12 Because they do not stimulate adrenergic receptors directly, they may be effective when added to catecholamines.

Diuretics should be used to treat pulmonary congestion and en- hance oxygenation. Vasodilators should be used with extreme caution in the acute setting because of the risk for precipitating further hypotension and decreasing coronary blood flow. After blood pressure has been stabilized, however, vasodilator therapy can decrease preload and afterload. Sodium nitroprusside is a balanced arterial and venous vasodilator that decreases filling pressures and can increase stroke volume in


patients with heart failure by reducing afterload. Nitroglycerin is an effective venodilator that reduces the pulmonary capillary occlusion pressure and can decrease ischemia by reducing left ventricular filling pressure and redistributing coronary blood flow to the ischemic zone.18 Both agents may cause acute and rapid decreases in blood pressure, and dosages must be titrated carefully; invasive hemodynamic monitoring can be useful in optimizing filling pressures when these agents are used.

THROMBOLYTIC THERAPY

Although it has been demonstrated convincingly that thrombolytic therapy reduces mortality rates in patients with acute myocardial infarction,', 27, 29 the benefits of this therapy in patients with cardiogenic shock are less certain. It is clear that thrombolytic therapy can reduce the likelihood of subsequent development of shock after initial presentation.', 27, 33 This finding is important because most patients develop cardiogenic shock more than 6 hours after hospital pre~entation.~~, 40

Nonetheless, no trials have demonstrated that thrombolytic therapy reduces mortality in patients with established cardiogenic shock. The numbers of patients are small because most thrombolytic trials have excluded patients who have cardiogenic shock at pre~entation.'~ In the GISSI trial,'3, 27 30-day mortality rates were 69.9% in 146 patients with cardiogenic shock who received streptokinase and 70.1% in 134 patients receiving placebo. The International Study Group reported a mortality rate of 65% in 93 patients with shock treated with streptokinase and a mortality rate of 78% in 80 patients treated with recombinant tissue plasminogen activator (rt-PA).41 In the GUSTO 315 patients had shock on arrival; mortality was 56% in patients treated with streptokinase and 59% in patients treated with rt-PA.40

Consideration of the efficacy of thrombolytic therapy once cardiogenic shock has been established makes the disappointing results in this subgroup of patients easier to understand. The degree of reperfusion correlates with outcome,42 and reperfusion has been shown to be less likely for patients in cardiogenic shock.6, 42 When reperfusion is successful, mortality has been shown to be reduced signifi~antly.~~ The lower rates of reperfusion in patients with shock may explain some of the disappointing results in this subgroup in the thrombolytic trials.

The reasons for decreased thrombolytic efficacy in patients with cardiogenic shock are not understood fully but probably include hemodynamic, mechanical, and metabolic factors. Decreased arterial pressure limits the penetration of thrombolytic agents into a th romb~s .~ Passive collapse of the infarct artery in the setting of hypotension can contribute to decreased thrombolytic efficacy, as can acidosis, which inhibits the conversion of plasminogen to p la~min .~ Two small studies2', 55 support the notion that vasopressor therapy to increase aortic pressure improves thrombolytic efficacy. The use of intra-aortic balloon pumping may increase the effectiveness of thrombolytics as well.

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INTRA-AORTIC BALLOON PUMPING

Intra-aortic balloon pumping (IABP) reduces systolic afterload and augments diastolic perfusion pressure, increasing cardiac output and improving coronary blood flow. These beneficial effects, in contrast to those of inotropic or vasopressor agents, occur without an increase in oxygen demand. IABP is efficacious for initial stabilization of patients with cardiogenic shock. Small randomized trials in the prethrombolytic era, however, failed to show that IABP alone increases sur~ival.'~, 54 IABP alone does not improve blood flow distal to a critical coronary stenosis s~bstantially.~~

Intra-aortic balloon pumping is an essential support mechanism to allow definitive therapeutic measures to be undertaken rather than an independent modality to treat cardiogenic shock. In the GUSTO trial, patients who presented with shock and had early IABP placement showed a trend toward lower mortality, even after exclusion of patients who underwent revasc~larization.~~ A similar trend was seen in the SHOCK trial registry.33 Several observational studies have suggested that IABP can improve outcome in patients with shock, although revascularization procedures are a confounding factor in these st~dies. '~, 47, IABP has been shown to decrease reocclusion and cardiac events after emergency angioplasty for acute myocardial infarct i~n.~~

In hospitals without direct angioplasty capability, stabilization with IABP and thrombolysis followed by transfer to a tertiary care facility may be the best management option. IABP may be a useful adjunct to thrombolysis in this setting by increasing drug delivery to the thrombus, improving coronary flow to other regions, preventing hypotensive events, or by supporting blood pressure and ventricular function until areas of stunned myocardium can recover. Two retrospective have shown that patients with cardiogenic shock who were treated in the community hospital with IABP placement followed by thrombolysis had improved in-hospital survival and improved outcomes after subsequent transfer for revascularization, although selection bias is clearly a confounding factor.

REVASCULARIZATION

Pathophysiologic considerations and extensive retrospective data favor aggressive mechanical revascularization for patients with cardiogenic shock owing to myocardial infarction. Recently, a landmark study (SHOCK presented prospective randomized controlled data addressing this issue.

Primary Coronary Angioplasty

Re-establishment of brisk (TIM1 grade 3) flow in the infarct-related artery is an important determinant of left ventricular function and sur-


viva1 after myocardial infarction.28 Direct percutaneous transluminal coronary angioplasty (PTCA) can achieve TIMI grade 3 flow in 80% to 90% of patients with myocardial compared with rates of 50% to 60% 90 minutes after thrombolytic therapy.28, 65 In the Primary Angio- plasty in Myocardial Infarction (PAMI) trial, which compared direct angioplasty with thrombolytic therapy, a mortality benefit for PTCA (in- hospital mortality rate, 2.0% versus 10.4%, P = 0.01) was seen in high- risk patients (age >70 years, large anterior myocardial infarction, heart rate Therefore, patients with cardiogenic shock are candidates for direct angioplasty. In addition to improving wall motion in the infarct territory, increased perfusion of the infarct zone has been associated with augmented contraction of remote myocardium, possibly because of recruitment of collateral blood

Retrospective analyses of angioplasty in patients with cardiogenic shock consistently have found that patients with successful reperfusion have much better outcomes than those without successful reperfusion.2, 6, 48, 67 In a subgroup analysis of the 2972 patients with cardiogenic shock in the GUSTO trial, 30-day mortality was significantly lower in patients who had angioplasty (43% compared with 61% for patients with shock on arrival, 32% compared with 61% for patients who developed In this trial patients treated with an “aggressive” strategy (coronary angiography performed within 24 hours of shock onset with revascularization by PTCA or bypass surgery) had significantly lower mortality (38% compared with 62%).6 This benefit was present even after adjust- ment for baseline characteristics6 and persisted to 1 year.7

The role of newer developments in PTCA for acute myocardial infarction in patients with cardiogenic shock remains to be defined. ,Recent reports have suggested that placement of coronary stents may improve outcome after failed or suboptimal PTCA or as a primary appr0ach.2~. The PAMI stent pilot trialM and the Intracoronary Stenting and Antithrombotic Regimens (ISAR)59 trials recently have shown that primary stenting is feasible in patients with acute myocardial infarction; TIMI grade 3 flow is restored in more than 90% of patients, and short- term outcome is good.63 Data from patients with cardiogenic shock are more sparse. A recent study of direct PTCA in patients with shock2 reported a success rate of 94%, with placement of stents in 47% of patients; the in-hospital mortality rate was 26%. Another study of stenting for failed angioplasty in patients with cardiogenic shock reported a mortality rate of 27y0.~*

The role of adjunctive antiplatelet therapy also is evolving. Platelet glycoprotein IIb/IIIa antagonists have been shown to improve short- term clinical outcomes after angioplasty, especially in patients at high risk for complications.16, l7 Published experience with IIb/IIIa receptor inhibition in patients with cardiogenic shock is limited to case reports to date,6O but extrapolation from other settings suggests that they may play an important adjunctive role in patients with shock who undergo angioplasty.

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Coronary Artery Bypass Surgery

Several trials have reported favorable outcomes for patients with cardiogenic shock who undergo coronary artery bypass surgery.15, Left main and three-vessel coronary disease are common in patients with cardiogenic shock,28, 33, 34 and the potential contribution of ischemia in the noninfarct zone to myocardial dysfunction in patients with shock would argue for complete revascularization. Nonetheless, the logistic and time considerations involved in mobilizing an operating team, the high operative morbidity and mortality, and the generally favorable results of percutaneous interventions all mitigate against routine bypass surgery for affected patients. In the series reported by DeWood and colleag~es,'~ IABP support was used successfully as a bridge to coronary artery bypass surgery. The roles of other supportive measures, such as emergency cardiopulmonary bypass, remain to be defined.

It is important to realize that these studies of revascularization in patients with cardiogenic shock were retrospective and uncontrolled. Selection bias is clearly present because patients selected for revascularization tend to be younger, less critically ill, and more likely to receive IABP support; they also tend to have less comorbidity.6, 33, 40 In addition, patients whose conditions deteriorate before planned revascularization is performed are counted in the nonrevascularized group. In the SHOCK trial registry, not only was mortality in patients selected for cardiac catheterization lower than in those not selected (51% compared with 85%), but mortality was also lower (58%) in catheterized patients who did not undergo revasc~larization.~~ A small, randomized study, the Swiss Multicenter evaluation of early Angioplasty for SHock (SMASH)

showed no significant difference in mortality rate between patients randomized to angioplasty and those who were randomized to medical treatment (69% compared with 78%), although the trial was stopped early because of difficulties in patient recruitment.

The recently reported SHOCK trial is a landmark study because it contains the only randomized, controlled, prospective data addressing revascularization in patients with cardiogenic The SHOCK trial randomly assigned patients with cardiogenic shock to receive optimal medical management, including IABP and thrombolytic therapy, or to cardiac catheterization with revascularization using PTCA or coronary artery bypass grafting (CABG).

The trial enrolled 302 patients and was powered to detect a 20% absolute decrease in 30-day all-cause mortality rates. Mortality at 30 days was 46.7% in patients treated with early intervention and 56% in patients treated with initial medical stabilization, but this difference did not reach statistical significance ( p = 0.11).34 At 6 months, the absolute risk reduction was 13% (50.3% compared with 63.1%, p = 0.027).34 Subgroup analysis showed a substantial improvement in mortality rates in patients younger than 75 years of age at 30 days (41.4% versus 56.8%, p = 0.01) and 6 months (44.9% versus 65.0%, p = 0.003).34

It is important to note that the control group (patients who received medical management) had a lower mortality rate than that reported in


previous studies; this may reflect the aggressive use of thrombolytic therapy (64%) and balloon pumping (86%) in these controls.34 These data provide indirect evidence that the combination of thrombolysis and IABP may produce the best outcomes when cardiac catheterization is not immediately available.

The SHOCK trial was underpowered to detect the primary end point (30-day mortality). This occurrence may have been because of a lower mortality rate among controls than might have been expected.% The improved survival with revascularization at 6 months and in patients younger than 75 years of age strongly supports the superiority of a strategy of early revascularization in most patients with cardiogenic shock (see Fig. 3).

OTHER CAUSES OF CARDIOGENIC SHOCK

Right Ventricular Infarction

Right ventricular infarction occurs in up to 30% of patients with inferior infarction and is clinically significant in Patients present with hypotension, elevated neck veins, and clear lung fields. Diagnosis is made by identifying ST-segment elevation in right precordial leads or by characteristic hemodynamic findings on right heart catheterization (elevated right atrial and right ventricular end-diastolic pressures with normal to low pulmonary artery occlusion pressure and low cardiac output). Echocardiography can demonstrate depressed right ventricular

Patients with cardiogenic shock on the basis of right ventricular infarction have a better prognosis than those with left-sided pump fai1u1-e.~~ This finding may be because right ventricular function tends to return to normal over time with supportive therapy,14 although such therapy may need to be prolonged.

In patients with right ventricular infarction, right ventricular preload should be maintained with fluid administration. In some cases, however, fluid resuscitation may increase pulmonary capillary occlusion pressure but may not increase cardiac output, and overdilation of the right ventricle can compromise left ventricular filling and cardiac out-

Inotropic therapy with dobutamine may be more effective in increasing cardiac output in some patients, and monitoring with serial echocardiograms also may be useful to detect right ventricular overdis- tention.14 Maintenance of atrioventricular synchrony also is important in these patients to optimize right ventricular filling.& For patients with continued hemodynamic instability, intra-aortic balloon pumping may be useful, particularly because elevated right ventricular pressures and volumes increase wall stress and oxygen consumption and decrease right coronary perfusion pressure, exacerbating right ventricular ischemia.

Reperfusion of the occluded coronary artery also is crucial. A study using direct angioplasty" demonstrated that restoration of normal flow resulted in dramatic recovery of right ventricular function and a mortal-

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ity rate of only 2%, whereas unsuccessful reperfusion was associated with persistent hemodynamic compromise and a mortality rate of 58%.

Acute Mitral Regurgitation

Ischemic mitral regurgitation usually is associated with inferior myocardial infarction and ischemia or infarction of the posterior papillary muscle. Papillary muscle rupture typically occurs 2 to 7 days after acute myocardial infarction and presents dramatically with pulmonary edema, hypotension, and cardiogenic shock. When a papillary muscle ruptures, the murmur of acute mitral regurgitation may be limited to early systole because of rapid equalization of pressures in the left atrium and left ventricle. More importantly, the murmur may be soft or inaudi- ble, especially when cardiac output is 10w.~

Echocardiography is extremely useful in the differential diagnosis, which includes free wall rupture, ventricular septal rupture, and infarct extension with pump failure. Hemodynamic monitoring with pulmonary artery catheterization also may be helpful. Management includes afterload reduction with nitroprusside and intra-aortic balloon pumping as temporizing measures. Inotropic or vasopressor therapy may be needed to support cardiac output and blood pressure. Definitive therapy, however, is surgical valve repair or replacement, which should be undertaken as soon as possible because clinical deterioration can be s ~ d d e n . ~ , ~

Ventricular Septa1 Rupture

Patients who have ventricular septal rupture have severe heart failure or cardiogenic shock, with a pansystolic murmur and a paraster- nal thrill. The hallmark finding with right heart catheterization is a left- to-right intracardiac shunt. With right heart catheterization, a "step- up" in oxygen saturation from right atrium to right ventricle can be demonstrated, but the diagnosis is made most easily with echocardiogra-

Rapid institution of intra-aortic balloon pumping and supportive pharmacologic measures is necessary. Operative repair is the only viable option for long-term survival. The timing of surgery is controversial, but most authorities now suggest that repair should be undertaken early, within 48 hours of the rupture?, 45

PhY.

Free Wall Rupture

Ventricular free wall rupture usually occurs during the first week after myocardial infarction; the classic patient is elderly, female, and hypertensive. Early use of thrombolytic therapy reduces the incidence of cardiac rupture, but late use actually may increase the risk. Free wall


rupture presents as a catastrophic event with a pulseless rhythm. Salvage is possible with prompt recognition, pericardiocentesis to relieve acute tamponade, and thoracotomy with repair.56

SUMMARY

Mortality rates in patients with cardiogenic shock remain frustrat- ingly high. Its pathophysiology involves a downward spiral in which ischemia causes myocardial dysfunction, which in turn worsens ischemia. Areas of viable but nonfunctional myocardium can contribute to the development of cardiogenic shock. Rapid diagnosis and prompt initiation of supportive therapy to maintain blood pressure and cardiac output, followed by expeditious coronary revascularization, are crucial. The SHOCK multicenter randomized trialM has provided important new data that support a strategy of emergent cardiac catheterization and revascularization with angioplasty or coronary surgery when feasible. This strategy can improve survival and represents standard therapy at this time. In hospitals without direct angioplasty capability, stabilization with IABP and thrombolysis followed by transfer to a tertiary care facility may be the best option.

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