Half-life = 0.5-2 h. Thrombocytopenia rare.
These agents increase cardiac contractility and enhance cardiac performance but often at the expense of an elevated myocardial oxygen demand. The sympathomimetic drugs have a similar rapid onset (<5 min) and peak effect (15 min) with a half-life of 1.5-2.5 min (113). Proarrhythmic actions are the most serious side effect. The pharmacodynamics of these drugs must be considered including the logarithmic increase in concentration necessary to produce linear increases in effect, the development of tolerance due to receptor desensitization and the complex interaction of individual agents upon the adrenergic receptor subtypes (114). The balance of inotropic, chronotropic, and vasoactive effects of each drug are optimally applied with accurate information regarding the patient's hemodynamic status.
Dopamine is usually the initial drug utilized in treating patients with cardiogenic shock. It is effective in increasing arterial pressure and raising cardiac output providing a necessary initial step in the patient with significant hypotension. The effectiveness of dopamine diminishes after 24 h, not only from receptor down-regulation, but also from depletion of norepinephrine stores (115). Dobutamine's b-effects increase cardiac output, reduce vascular resistance and pulmonary capillary wedge pressure, but without alteration in arterial pressure (116). Norepinephrine is usually reserved for patients with very severe hypotension or those who fail to respond to other inotropic agents. It can effectively improve coronary perfusion by increasing arterial pressure (117). Epineph-rine is a potent inotropic agent but use may be limited by tachycardia and ventricular arrhythmias (114). Phenylephrine is an a-1 vasoconstictor agent that should be reserved for shock with a loss of vascular tone. It is contraindicated for patients with a systemic vascular resistance of >1200 dynes • s/cm-5 (118). The phosphodiesterase inhibitors amrinone and milrinone have positive inotropic and significant vasodilator actions producing a rise in cardiac output, a fall in left ventricular filling pressure, with minimal effect on myocardial oxygen demand. However there is a risk of significant hypotension with these agents, and they possess a long half-life (119).
By combining agents therapy may achieve the advantages of modest inotropic doses while minimizing the risk of side effects. Dopamine and dobutamine have often been utilized together to optimize the benefits of each drug. Both drugs infused at a rate of 7.5 ^g/kg/min have been shown to achieve a more ideal hemodynamic state than higher doses of either drug alone in patients with cardiogenic shock (120). Other drugs can also be utilized in combination, such as norepinephrine and low-dose dopamine, to maintain arterial pressure and renal perfusion. The addition of a phophodiesterase inhibitor may further improve cardiac output in patients on sympathomimetic drugs. Vasodilators, such as nitroprusside, may be used cautiously in patients with an adequate arterial pressure but a low cardiac output. Diuretics are utilized in an ongoing fashion to optimize left ventricular filling pressures. A vigilant attention to the patient's status is critical to avoid wide variations in hemodynamic parameters that may lead excessive drug doses, proarrhythmia, and catastrophic deterioration.
The loss of vascular tone in the late phases of all types of shock has been noted (77). Vasopressin has been utilized in shock associated with refractory cardiac arrest (121). A nitrous oxide synthetase inhibitor, L-NMMA has been infused in patients with "refractory cardiogenic shock," leading to a significant increase in mean arterial pressure (+43%) although a transient drop in cardiac output was noted that rose after 5 h (122). A small (n = 22) randomized trial demonstrated a favorable effect on hemodynamic status and survival (123).
Other innovative pharmacological advances may be proven effective in the future. The incremental benefits of limiting reperfusion injury may prove substantial in cardiogenic shock. Several methods have been examined to impede oxygen-free radical damage utilizing oxygen radical scavengers, adenosine, and neutrophil inhibitors (antibodies to adhesion receptors or selectin blockade) (32,33,124,125).
Myocardial metabolism is not only altered within the infarct zone, but also in remote regions with or without ongoing ischemia (49,126). "Substrate" infusions of gluta-mate/aspartate, glucose-insulin-potassium, coenzyme Q10 and 2-mercato-propionyl-glycine have restored remote myocardial function in an experimental model of cardiogenic shock (127). Carnitine may protect myocardial metabolism in ischemia (128). A survival of 78% was reported for 27 patients receiving high doses of intravenous L-carnitine (129). Meta-analysis of trials evaluating the use of glucose-insulin-potassium in myocardial infarction have suggested a benefit, for applying these citric acid cycle-repleting techniques to patients with cardiogenic shock (130-132). Ongoing clinical investigation will examine the benefits of these approaches.
Mechanical Support of the Circulation Intra-Aortic Balloon Counterpulsation
Intra-aortic balloon counterpulsation has been utilized to treat patients with cardiogenic shock for the past 30 yr. Experimental augmentation of coronary diastolic flow was described by Kantrowitz and Kantrowitz in 1953 (133). The application of this principle was reported by Claus and colleagues (134) utilizing a device that cycled blood in the aorta. The gas-driven balloon displacement pump introduced in clinically by Kantrowitz et al. in 1968 (135) has persisted as an essential adjunct in the therapy of patients with cardiogenic shock.
By inflating the balloon catheter during diastole coronary perfusion pressure increases, and the collapse of the balloon with the onset of systole results in a decline in left ventricular afterload. Hemodynamic effects in cardiogenic shock include a reduction systolic aortic pressure and a rise in diastolic aortic pressure, with no change in mean aortic pressure (136). Cardiac output improves and heart rate decreases. The reduction in afterload is beneficial to patients with mechanical complications (mitral regurgitation and ventricular septal defect) (137). Overall, there is a decline in myocar-dial oxygen demand with a reduction in diastolic left ventricular pressure and volume (138,139). Coronary sinus lactate levels are decreased with counterpulsation indicating a beneficial effect on myocardial energetics (136,140).
Counterpulsation increases coronary driving pressure with a resultant rise in coronary blood flow (138,140). Although there is controversy regarding the efficacy of this technique to increase flow beyond a coronary obstruction, variations in experimental preparations or clinical conditions along with differences in coronary flow measurements may account for these discrepancies (138,141,142). In theory, regional perfusion may be enhanced to remote myocardium through a subcritical compliant stenosis or via collateral circulation (30,138,143). Counterpulsation alone has not been shown to decrease infarct size in acute infarction (144), but theoretically, may minimize the "piecemeal" extension of necrosis induced by the shock state.
The use of the intra-aortic balloon pump will result in hemodynamic stabilization of >75% of patients with medically refractory cardiogenic shock (136,145,146). Despite these benefits, the intra-aortic balloon pump appears to be underutilized in
patients with cardiogenic shock, although the proportion appears to be increasing (Fig. 4) (12,14,147-149).
Although counterpulsation is an ACC/AHA Class I recommendation for cardiogenic shock (108), the independent effect of this support on survival in remains controversial. Early studies noted a persistent high mortality rate of patients treated with shock. For example, a cooperative trial of 87 patients reported a 77% hospital mortality in 1969 (136). Other investigation also suggested little survival benefit despite the marked clinical improvement (150). In most studies, counterpulsation was often applied many hours after shock had developed and nearly always after a failure of intense vasopressor support.
In the modern era of infarct reperfusion therapy, interventional procedures (throm-bolysis, angioplasty, bypass surgery) are often combined with counterpulsation. Observational studies have demonstrated an association with a lower hospital mortality in patients receiving balloon pump support (151). However, patients treated with balloon pump support are often younger with fewer comorbidities (148,149). The combination with emergency coronary bypass surgery has been used to treat patients with cardio-genic shock successfully for three decades (152-154). Clear discrimination of a unique benefit for counterpulsation is more complex with these common coexistent treatment variables.
The utilization of intra-aortic balloon pump support and thrombolysis appears to have a unique synergistic effect (see Thrombolysis section below). A favorable trend on 30-d and 1-yr mortality was noted with early counterpulsation in the GUSTO-I trial (155). Combined analysis of the GUSTO-I and GUSTO-III shock patients demonstrated an improved 30-d survival with balloon pump support (45 vs 58%, p = 0.001) regardless of patient age (156). Evaluation of 5563 shock patients who received thrombolysis in the NRMI-2 database revealed a significant reduction in mortality for patients undergoing counterpulsation (49 vs 67%) (148). This positive effect of balloon pump support on mortality reduction for shock patients treated with thrombolysis was also evident in the SHOCK registry (47 vs 63%, p < 0.0001) (149).
In contrast to the relatively defined benefit for counterpulsation with thrombolysis, the survival advantage in combination with primary angioplasty is less apparent. No survival improvement was seen in the SHOCK registry, and a higher mortality (47 vs 42%, p < .01) was noted in the NRMI-2 registry (148,149). This may reflect a more favorable clinical status of patients undergoing primary angioplasty without balloon pump support. Furthermore, the intra-aortic balloon pump improves the safety of cardiac catheterization and primary angioplasty during cardiogenic shock. Brodie et al. noted fewer adverse catheterization laboratory events in patients with cardiogenic shock (14.5 vs 35.1%, p = 0.009) in patients undergoing counterpulsation before intervention (157).
The hazards of intra-aortic balloon counterpulsation must be considered. Major complications (10-20%) are primarily related to limb ischemia or hemorrhage requiring surgery and/or transfusion (158). Other major complications include death (<1%), thromboembolism, aortic dissection, sepsis, cholesterol embolization, stroke, and limb loss. Female gender, peripheral vascular disease, diabetes mellitus and body surface area are predictors of complications (158-160). Intra-aortic balloon pump complications are not more frequent in shock patients (161).
Intra-aortic balloon counterpulsation remains an important adjunct for the support of patients with cardiogenic shock. The relative benefit of balloon pump support is uncertain. Although randomized investigation is needed, it remains difficult to conduct in these critically ill patients. Notably, the less than expected benefit of revascularization in the SHOCK trial has been attributed to the uniform aggressive supportive therapy utilized, which included balloon counterpulsation (86% in both treatment arms) (6).
Although adequate circulation can be restored in many patients by intra-aortic balloon counterpulsation, approx 25% will fail to improve and a stable cardiac rhythm is necessary for continued effectiveness (136). Several innovative techniques have been introduced to extend hemodynamic support to even the most critically ill patients. These methods have been utilized to allow time for recovery of ischemic border zone myocardium or favorable remodeling processes (162) and provide an opportunity for corrective procedures, such as revascularization or as bridge therapy prior to transplantation.
The ideal mechanical support device should maintain an adequate cardiac output, improve coronary perfusion, and decrease myocardial oxygen consumption while allowing rapid, uncomplicated, safe implementation. While no device fulfills all of these criteria, several have effectively supported critically ill patients.
Peripheral cardiopulmonary bypass has been used to support patients in cardiogenic shock (163-167). The main components of the percutaneous cardiopulmonary bypass support (PCPS) include, a centrifugal nonocclusive pump, hollow-fiber membrane oxy-genator, and a heat exchanger. Femoral arterial and venous access is obtained via 18-20 French cannulas. The PCPS can achieve flow rates of up to 6 L/min. This technique can be rapidly instituted in the catheterization laboratory or at the bedside and can be applied to patients in cardiac arrest.
PCPS has been utilized primarily to support patients undergoing elective high risk angioplasty. In these patients bypass support results in a reduction of left ventricular afterload and left ventricular systolic volume with no change in mean arterial pressure (summation of a fall in systolic and rise in diastolic pressure). However, there is deterioration of regional myocardial function in areas supplied by stenotic vessels (168).
Other limitations include difficult application with significant peripheral vascular disease and inadequate ventricular unloading (169). Complications of PCPS are principally related to hemorrhage at the access sites. A time limitation of 6-8 h has been recommended with PCPS due to an increased risk of metabolic abnormalities, hemolysis, and disseminated intravascular coagulation. However, success has been reported with more prolonged (29 ± 26 h) use of this device in cardiogenic shock when combined with revascularization (166). Other forms of extracorpeal membrane oxygenation support have been reported (169).
Shawl and colleagues reported institution of bypass within 30-180 min of shock onset (4.4 h from infarct onset) in 8 patients, with 100% survival in all 7 patients who underwent revascularization at 8 mo (163). Other small series have also reported success with this technique (166,167,170).
The Hemopump support device consists of a continuous flow pump based on an Archimedes screw principle, contained within a 14 or 21 French catheter. The pump rotates at 27,600-45,000 rpm propelling blood from a vent within the left ventricle to the aorta. The larger device allows flow rates up to 3.5 L/min, whereas the smaller per-cutaneously inserted 14F device is limited to rates of 1.7-2.2 L/min (171-173). The Hemopump has been shown to effect significant ventricular unloading, while improving regional function to ischemic and reperfused myocardium (174,175). The device can be utilized for several d. Its use is also limited by peripheral vascular disease and is con-traindicated with significant aortic vascular or aortic valve disease. Complications are primarily related to thrombocytopenia requiring platelet transfusion (7%), thromboem-bolism (9.6%), and ventricular arrhythmias (27%) (176).
In a series of 11 patients with cardiogenic shock, there was a significant rise in mean arterial pressure and a fall in left ventricular end-diastolic pressure. Four of the 11 patients survived despite performance of revascularization procedures in 10 out of 11 patients (177). This device is no longer available in the United States.
A variety of ventricular assist devices have been utilized to support patients in cardiogenic shock. Biventricular support is usually not necessary in this setting (178). These devices provide sufficient hemodynamic support and can unload the left ventricle potentially reducing infarct size (178-180). Long-term support can be achieved, but a thoracotomy is usually required. Other less invasive (including percutaneous application) assist devices have been introduced utilizing inflow from the left atrium, via a transeptal catheter, with return to an arterial cannula (181-183). However, experience is limited.
These devices provide a considerable increment in circulatory support compared to the intra-aortic balloon pump and can sustain prolonged survival, provided they are implemented before shock-induced irreversible organ damage. Despite left ventricular unloading and, theoretically, an opportunity for myocardial healing (184) and recovery, only a few patients have undergone device explantation unless utilized as a bridge to transplantation (178,185). This latter approach has been utilized successfully in several series (178,185-188).
The myocardial salvage and survival benefits of achieving a patent infarct artery have established the importance of reperfusion therapy for myocardial infarction (2,189,190). This concept remains at the foundation of modern therapy for acute myocardial infarc-
tion A critical link was established between early attainment of complete (TIMI 3 flow) infarct artery patency and survival by the GUSTO-I angiographic substudy (191). Intuitively, one would predict a similar salutary connection between early patency and survival in cardiogenic shock. In a series of 200 patients with cardiogenic shock, the mortality rate in patients with patent infarct arteries was 33 vs 75% with closed arteries (93). Recent data from the SHOCK registry verified the relationship between complete infarct artery patency and survival (Fig. 5) (18). The strong association between infarct artery patency and outcome highlights a meaningful achievable target in the progress toward improving the survival of cardiogenic shock.
Recent large population studies have demonstrated improving survival of patients with shock. In the Worcester Heart Attack Study, mortality fell from 70-85% between 1975-1990 to 50-60% in 1995-1997. This was associated with a substantial increase intra-aortic balloon counterpulsation (5 ^ 42%), thrombolysis (0 ^ 25%), angioplasty (0 ^ 29%), and coronary bypass surgery (0 ^ 14%) (12). In a similar fashion, patients surviving shock were more likely to undergo revascularization procedures in the NRMI-2 registry (5). A comparable benefit from more extensive use of interventions, including revascularization, has been postulated to explain the lower mortality for patients in the GUSTO-I trial with shock hospitalized in the U.S. compared with other countries (192). Despite this evidence and recent trial data (6), there remains skepticism (primarily due to concerns about selection bias) regarding the advantage of reperfusion therapy in patients with cardiogenic shock (193).
The mortality reduction by thrombolytic therapy for acute myocardial infarction led to hopeful speculation that these agents favorably influence the survival of the subgroup with cardiogenic shock. It appears that thrombolysis does reduce the incidence of car-diogenic shock. In the Anglo-Scandinavian Study of Early Thrombolysis (ASSET)-1
trial, the incidence was reduced from 5.1 to 3.8% (p < 0.05) with tPA (190). Shock (onset >24 h after admission) was also decreased with treatment in the anistreplase (APSAC) multicenter trial from 9.5 to 3.2% (p = 0.03) (194).
An analysis of 94 thrombolytic trials involving 81,005 patients with myocardial infarction noted that 22% included patients with cardiogenic shock (195). Only 3 trials performed subgroup analysis on this complication and one trial reported data comparing thrombolysis with a control group. The Gruppo Italiano per lo Studio della Streptochi-nasi nell'Infarto Miocardico (GISSI) trial reported data regarding the effect of intravenous streptokinase on patients with defined cardiogenic shock, and no benefit on hospital survival was identified with treatment (n = 280, mortality: streptokinase 69.9%, untreated 70.1% p = NS) (2). However, both the APSAC Intervention Mortality Study (AIMS) and the ISIS-2 (streptokinase) trials reported a survival benefit for treatment with these agents in patients with hypotension with a 33 and 23% reduction in mortality, respectively (189,196). Likewise, the Fibrinolytic Therapy Trialist analysis noted that the absolute benefits of thrombolysis are largest in patients with evidence of hemodynamic impairment identified by hypotension, defined by a systolic blood pressure <100 mmHg (60 lives saved/1000 patients treated) or the combination of hypotension and tachycardia, heart rate (HR) >100 beats/min (bpm) (73 lives saved/1000 patients treated) (197). Nevertheless, the mortality of the relatively small number of patients with shock or hypotension remained high in the major thrombolytic therapy trials.
The equivocal or marginal benefit apparent in these trials may reflect the diminished efficacy of thrombolysis in cardiogenic shock. A reperfusion rate of 44% was reported for 44 cardiogenic shock patients receiving intracoronary streptokinase in the Society for Cardiac Angiography's registry compared to an overall reperfusion rate of 71% (198). Bengston et al. reported similar results with a patent infarct artery found in 48% (33 out of 69) of patients receiving intravenous thrombolysis (93). The effectiveness of thrombolysis is determined by complex mechanical, hemodynamic, and metabolic factors. For example, acidosis can impair the transformation of plasminogen to plasmin decreasing the efficacy of thrombolytic agents in circulatory shock (199).
The reduction of coronary perfusion pressure occurring with cardiogenic shock interferes with the delivery of plasminogen and plasminogen activators to the thrombus (200). Experimental data with magnetic resonance imaging have demonstrated enhanced lysis with pressure-induced permeation of whole blood thrombi (201). Both norepinephrine infusion and intra-aortic balloon counterpulsation have been shown to augment coronary thrombolysis in intact animal models (202-204). This principle of pressure-dependent thrombolysis has been extended to the clinical setting. Garber et al. (205) reported successful thrombolysis (tPA) in cardiogenic shock patients who responded to dopamine or norepinephrine with a rise in mean arterial pressure (64-102 mmHg, 6 of 8 patients treated). A small retrospective community hospital series has demonstrated an improved survival of patients who underwent combined thrombolysis and counterpulsation compared with either treatment alone (n = 36; combined 40%, intra-aortic balloon pump 10%, thrombolysis 6%, p = 0.04), all without angioplasty or surgery (206). This combined strategy may play an important role in hospitals without revascularization facilities by stabilizing patients and facilitating their transfer to tertiary centers (207). The synergistic benefits of intra-aortic balloon counterpulsation and thrombolysis have been previously detailed (see Intra-aortic Balloon Counterpulsation section).
Differences have been noted in the relative efficacy of thrombolytic agents in cardiogenic shock. Patients receiving accelerated tPA were less likely to develop cardiogenic shock in the GUSTO-I trial (5.5%) compared to those treated with streptokinase (6.9%) (p < 0.001) (3). However, there was a trend for a lower 30-d mortality in those who developed shock and were treated with streptokinase and subcutaneous heparin compared with tPA (51 vs 57%, p = 0.061). A similar advantage for streptokinase was noted in the International Study Group (208). The mortality of patients with shock treated with retaplase is equivalent to tPA therapy (209).
The exclusion criteria and selection bias present in most trials of thrombolytic therapy have led to an incomplete understanding of its role in treating patients with cardiogenic shock. Patients who experience successful reperfusion of the infarct artery with throm-bolysis will likely attain a survival benefit. The hospital mortality was reduced overall in patients treated with thrombolysis in the SHOCK registry (54 vs 63%, p = 0.05) (149) and as noted, survival was further enhanced with balloon pump support. Thrombolysis especially when combined with intra-aortic balloon counterpulsation is an important initial treatment modality at hospitals without revascularization capabilities.
Reperfusion of an occluded infarct artery by primary angioplasty offers several advantages over thrombolytic therapy. These include superior reperfusion efficacy, near-elimination of the risk of intracranial hemorrhage, and reduction of recurrent ischemia and/or infarction (210). There are also benefits to this reperfusion method in the elderly, patients with prior bypass surgery, and in those who are ineligible for thrombolysis. Meta-analysis of randomized controlled trials has shown an advantage for primary angioplasty over thrombolysis with a reduction in mortality, reinfarction, and stroke (211). The reduced effectiveness of thrombolysis in cardiogenic shock has led to a presumed superiority of primary angioplasty as a reperfusion modality.
A review ofnonrepetitive patient series (Table 5) (44,45,47,48,93,212-229) examining balloon angioplasty in cardiogenic shock demonstrates considerable improvement in the hemodynamic parameters of patients undergoing successful angioplasty, with a reduction in left ventricular filling pressure and a rise in cardiac output (214,217,219,230-232). A significant increase in left ventricular ejection fraction has also been reported (223,231,233).
Although, superior to thrombolytic therapy, reperfusion efficacy in cardiogenic shock is decreased compared to the >90-95% success reported in the overall patient population undergoing primary angioplasty (210). For example, in the SHOCK registry, angioplasty was successful (defined as TIMI flow grade 2 or 3 with a residual stenosis <50%) in 75% with <TIMI grade 3 flow in 18% (223).
Examination of these series (Table 5) suggests that survival is enhanced by angio-plasty. These studies consistently demonstrate a lower mortality for patients undergoing successful angioplasty compared with historical controls, concurrent patients who do not undergo angioplasty, or fail the procedure. There are concerns regarding selection bias in these reports. Patients who are more critically ill or die prior to attempted revascularization may be excluded. A lower risk group may be selected for angiography. In both the GUSTO-I trial and SHOCK registry, patients who underwent catheterization without revascularization had an improved survival over those who did not undergo invasive evaluation (3,234). Consecutive application of angioplasty in a series (n = 25)
Angioplasty and Cardiogenic Shock
Mortality (%) Stent
Series Thrombolysis Reperfusion Time Hosp/ Successful Unsuccessful Long MVD Support reference N Age (%) (%) (h) 30d RP RP Term (%) Yr (%)
Series Thrombolysis Reperfusion Time Hosp/ Successful Unsuccessful Long MVD Support reference N Age (%) (%) (h) 30d RP RP Term (%) Yr (%)
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