Management of Cardiogenic Shock Complicating Acute Myocardial Infarction.
Pankaj Jariwala, Pravir Lathi, G. Ramesh, K. Sarat Chandra
INTRODUCTION
Cardiogenic shock is an important cause of in-hospital mortality after AMI. Though Cardiogenic shock commonly occurs following AMI or ischemia, there are multiple other causes producing this final common pathway leading to death. Cardiogenic shock may present on admission or may develop after admission. The timing of presentation depends upon the pathophysiology behind the disease involved. 1
Cardiogenic shock occurs approximately in 5-8 % of patients admitted with diagnosis of AMI. The incidence of cardiogenic shock has not decreased over period of time despite decrease in the mortality after AMI with increasing use of early revascularization. Several trials in the recent past have shown that early revascularization strategies are useful and improve 6 and 12 month mortality among those who survived. 2
INCIDENCE
The incidence of CS remained approximately 7-8% between 1975 and 1988 in a community in Worcester, Massachusetts, USA, where 14% of patients received thrombolytics 3 . The incidence of CS in the Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries (Gusto 1) trial, in which all patients received thrombolysis was 7.3 % 4 .
The extent of myocardial salvage from reperfusion treatment decreases exponentially with time to re-establishing coronary flow. Unfortunately, there has been little progress in reducing time to hospital presentation over the past decade 5
and this perhaps accounts for the stagnant incidence of cardiogenic shock in community studies (7.1%). 6 Cardiogenic shock also complicates non-ST elevation acute coronary syndromes. The incidence of shock in the PURSUIT trial was 2.9% (which excluded ST-elevation MI) 7 similar to the 2.5% incidence reported in the non- ST elevation arm of the GUSTO II-B trial (199495). 8
CS continues to complicate approximately 5% to 8% of STEMI and 2.5% of non- STEMI cases 7,9,10 . PROGNOSIS The 7.2% of patients developing shock in the GUSTO-I trial accounted for 58% of the overall deaths at 30 days. 11 Similarly, the 30 day death rates with non-ST elevation MI cardiogenic shock in the PURSUIT and GUSTO-II b databases were 66% and 73%, respectively. Even with early revascularization, almost 50% die at 30 days. The historic control mortality for CS complicating AMI is 80% 12,13 . From 1975 to 1988, which antedates the widespread use of reperfusion therapy, mortality rate has been consistently high at 78% 3 .
PATHOPHYSIOLOGY
Cardiogenic shock complicating acute MI is caused by predominant left ventricular failure in 80% of cases 14,15 . In the remaining 20%, shock results from right ventricular infarction or mechanical complications of MI, including ventricular septal rupture, acute mitral regurgitation, and free wall rupture. In patients who have predominantly left ventricular failure, extensive necrosis is evident and involves more than 40% of the left ventricle on autopsy 16 . 1 In many patients, acute occlusion of the left anterior descending artery is the culprit lesion and, in two thirds of all patients, multi-vessel disease is present 17 . The precipitating event leading to CS may not necessarily be a massive MI secondary to a single arterial occlusion, but the result of multiple small MIs with the final myocardial insult leading to a sudden loss of critical functioning myocardial mass 17,18 . Infarct expansion and re-infarction have been identified as important risk factors for development of shock in STEMI and non-STEMI. In settings of low coronary blood flow, thrombus may propagate to involve side branches and increase infarct size. MI is a hyper-coagulable clinical state, and re-occlusion of re-canalized arteries leading to re-infarction can occur in upto 20% of patients undergoing thrombolytic therapy and 2% of patients post-PCI. Patients who experience reinfarction have significantly increased chance of developing cardiogenic shock 19,20 .
The progressively downward course that describes the clinical deterioration of patients who have cardiogenic shock is shown in Fig.1 21,15 The leading event of ischemia and infarction leads to systolic and diastolic heart failure which involves the entire circulatory system with compensatory mechanisms setting in which leads to classical paradigm of circulatory shock. The systemic inflammatory response syndrome involves many inflammatory markers part of neurohormonal and cytokine system in perpetuation of shock. 22 This leads to hypoperfusion of all organs, particularly vital organs including heart, brain and kidneys. The coronary perfusion pressure decreases further and adds to the already existing state. The initial insult of ischemia leads to stunned myocardium. Most of the patients having multivessel disease already had hibernating myocardium which also contributes to the functional loss of myocardium. The ability of the unaffected myocardium to be recruited to preserve left ventricular function is impaired. 23
To increase cardiac output, the heart rate increases, thereby increasing myocardial oxygen consumption directly and affecting coronary perfusion. As heart rate increases, the time spent in diastole decreases. The time for tissue perfusion decreases resulting in further ischemia of the subendocardium. The wave front of ischemia results in eventual global dysfunction and the spiral deterioration continues. The resulting stuttering ischemia and infarction eventually results in left ventricular failure and death. 23
CLINICAL RECOGNITION Early recognition of left ventricular (LV) failure and low output state, the preshock phase, is crucial for the success of treatment and outcome. The pre-shock phase is not easily recognizable. Although CS is routinely diagnosed when hypotension develops, high systemic vascular resistance can maintain reasonable systemic arterial pressure even when severe depression of stroke volume and end organ hypoperfusion are present. A useful clue is tachycardia, which is often due to a low stroke volume. Confirmation of the diagnosis is the most important step in the management of these patients. 24 In the SHOCK trial registry, 64% of patients presented with hypotension, evidence of ineffective cardiac output (resting tachycardia, altered mental status, oliguria, cool peripheries), and pulmonary congestion. 25 A substantial minority (28%) presented with evidence of hypoperfusion in the absence of pulmonary congestion the silent lung syndrome. These latter patients have an equal distribution of anterior (50%) and non-anterior index infarctions (50%) with pulmonary capillary wedge pressure in the range of 21.56.7 mm Hg. 2
DIAGNOSTIC CRITERIA OF CARDIOGENIC SHOCK Cardiogenic shock is clinically defined as a state of end-organ dysfunction caused by hypoperfusion secondary to low cardiac output with associated hypotension, classically defined as a systolic blood pressure less than 90 mm Hg. 26 Hochman et al proposed criteria for diagnosis of cardiogenic shock as shown in box 1.
The presence of clinically cardiogenic pulmonary edema itself is evidence of increased left ventricular end diastolic pressure. 26 CS should be diagnosed in all patients exhibiting signs of inadequate tissue perfusion irrespective of blood pressure.
OTHER CAUSES OF CARDIOGENIC SHOCK There are several possible causes of cardiogenic shock in the setting of MIleft ventricular dysfunction, right ventricular dysfunction, and mechanical complications. Ventricular septal rupture, contained free wall rupture, and papillary muscle rupture. Mechanical complications must be strongly suspected in patients with CS complicating nonanterior MI, particularly a first MI. Hemorrhage, infection, and/or bowel ischemia may contribute to shock in the setting of MI. As with mechanical complications, a high index of suspicion is required to make these diagnoses in MI patients.
MANAGEMENT OF CARDIOGENIC SHOCK FOLLOWING AMI The treatment of cardiogenic shock patients consists of medical therapy, percutaneous revascularization procedures, cardiac surgery, and the implantation of devices.
Right Heart Catheterization Right heart catheterization is often not necessary for diagnosis and need only be performed when there is continued doubt or to guide management when shock does not rapidly resolve. There is retrospective data on increased mortality hazard associated with this procedure 27 . On the other hand, data from the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO-I) trial 28 and the Should We Emergently Revascularize Occluded Coronaries in Cardiogenic Shock ? (SHOCK) registry 29 suggest that it is not harmful, and possibly beneficial, in terms of outcome. The current American and European guidelines recommend right heart catheterization for patients who have ST-elevation acute coronary syndromes (ACS) and who have progressive heart failure, cardiogenic shock or mechanical complications, despite the paucity of evidence proving its efficacy 30,31
Echocardiography Doppler echocardiography is of paramount importance for hemodynamic assessment and for the evaluation of cardiac function, valvular status, and mechanical complications of ACS. 32 Perhaps this noninvasive, readily available method has supplanted right heart catheterization use in most situations. Echocardiography in cardiogenic shock can help to Evaluate left ventricular function and myocardium at risk Evaluate remote myocardial segments Screen for ventricular septal rupture Screen for severe mitral regurgitation and proceed to transoesophageal echocardiography as needed Look for tamponade/rupture Assess right ventricular function
TREATMENT In the early 80s, individual or single centre observational data on early 3 revascularization strategy benefiting patients with cardiogenic shock after AMI were published, but large scale trials were needed to prove the point. Hence, the National Heart, Lung, and Blood Institute funded the SHOCK trial in the USA, while the SMASH trial in Switzerland evaluated the same issue. 33,34 While SMASH failed to recruit an adequate number of patients, SHOCK reported an increase in 30 day survival from 46.7% to 56.0% by the adoption of an early revascularisation strategy, but this absolute 9% difference did not reach significance (p =0.11). On follow up, the survival difference in favour of the early revascularisation strategy became larger and significant at six months (36.9% v 49.7%, p =0.027) and one year (33.6% v 46.7%) for an absolute reduction of 13.2% (95% CI 2.2% to 24.1%, p <0.03) Fig.2 The benefit of early revascularisation was large for those <75 years at 30 days. Kaplan-Meier curve showing 12 month survival in the early revascularization and initial medical stabilization arms of the SHOCK trial. 82
General Care and Resuscitation These include correction of hypovolemia, hypoxemia, acidosis, Aspirin and intravenous Heparin. The most important step is maintenance of mean arterial pressure to prevent further damage to the vital organs and halt the perpetuation of circulatory shock. A mean arterial pressure of 60 mm Hg is generally necessary for tissue perfusion. 35 Intra-arterial measurement of blood pressure is advisable. Large-scale controlled studies have not been performed to compare different combinations of inotropes in patients who have cardiogenic shock.
Inotropes Dopamine and Dobutamine are the most commonly used inotropic agents. Dopamines myocardial inotropic and chronotropic effects are mediated through myocardial beta-1 adrenergic receptors, and are most evident with doses above 5 micrograms/kg/minute. The theoretical advantage of nephroprotective effect has been not been proved in one of the recent trials. 36 Dobutamine has both alpha and beta-adrenergic agonistic activities. It increases myocardial contractility through beta adrenergic receptor stimulation, with only a minute peripheral vasodilatory effect. The drug is usually initiated at 2 micrograms/kg/minute and titrated upwards according to the patients response, usually to a maximum of 20 micrograms/kg/minute. Dobutamine is often used together with low-dose dopamine for the inotropic effect of the former and suggested renal vasodilator effect of the latter. Norepinephrine is a potent alpha adrenergic agonist with less marked beta-1 adrenergic agonistic properties and a short half-life of 2 to 4 minutes. Vasoconstriction is dose-related, and the drug infusion is titrated upwards from an initial low dose of 0.02 to 0.04 microgram/kg/minute to a dose that maintains adequate systemic blood pressure. Norepinephrine may be used in conjunction with dopamine and dobutamine; however, the cardiac effects of these agents include worsening ischemia and serious arrhythmias, and the vasoconstriction induced by norepinephrine can lead to end-organ ischemia. Thus, one should avoid prolonged triple or double inotropic treatment.
Milrinone, a second-generation phosphodiesterase inhibitor, can be used in cardiogenic shock patients. Milrinone prevents the breakdown of cyclic adenosine monophosphate (cAMP), the final common pathway for raising intracellular calcium, thus increasing inotropy. The significant vasodilatory effect and relatively long plasma half-life make Milrinone difficult to use as 4 monotherapy in patients who have cardiogenic shock. Milrinone can be used synergistically with other inotropic drugs to enhance myocardial contractility 37 . Levosimendan represents a new class of positive inotropic agents. Levosimendan causes conformational changes in cardiac Troponin C during systole, leading to sensitization of the contractile apparatus to calcium ions 38,39 . In addition to its positive inotropic action, Levosimendan possesses vasodilating properties that reduce cardiac preload and afterload. Moreover, coronary blood flow is enhanced and myocardial oxygen supply is increased 40,41 . At present, however, use of levosimendan is not recommended by the manufacturer for the sole treatment of cardiogenic shock, because of its vasodilatory properties. Based on effects of vasopressin in septic shock 42 , J olly and colleagues 43
hypothesized that vasopressin would increase mean arterial pressure without altering pulmonary capillary wedge pressure or cardiac index. In a cohort of patients who developed refractory cardiogenic shock after myocardial infarction, vasopressin was associated with increased mean arterial pressure and no adverse effect on other hemodynamic parameters 43 .
Randomized prospective trials are warranted to confirm the utility and safety of vasopressin in the setting of cardiogenic shock after myocardial infarction. Other measures including fluids and diuretic therapy need intensive measurement of pulmonary wedge pressure with the help of right heart catheterization and hourly measurement of urine output. Arterial blood gas and oxygen saturation should be monitored with early institution of continuous positive airway pressure or mechanical ventilation as needed. The ECG should be monitored continuously, and defibrillating equipment, intravenous Amiodarone, and Lidocaine should be readily available. Thirty three per cent of patients in the early revascularization arm of the SHOCK trial had cardiopulmonary resuscitation, sustained ventricular tachycardia or ventricular fibrillation before randomization. 33 Mechanical Circulatory Support Mechanical circulatory devices play an important role in providing temporary support for patients in CS. Mechanical devices are superior to pharmacological therapy in CS in that perfusion is supported without increasing myocardial work and oxygen consumption. Intra-Aortic Balloon Counterpulsation Intraaortic balloon counter pulsation (IABP) is the most commonly used circulatory support device. A large, nonrandomized cooperative study in the prethrombolytic era showed that IABP counterpulsation alone, without adjunctive percutaneous coronary angioplasty (PTCA) or coronary artery bypass graft surgery (CABG) did not reduce mortality rates, which remained disappointingly high at 83% 44 . IABP therapy was, however, highly effective in initial clinical stabilization of patients, reversing end- organ hypoperfusion in patients with AMI and CS who proved refractory to vasopressor therapy 44 . Recent reports have suggested that IABP may be combined with thrombolytic therapy to improve reperfusion rates when CS is present, with improvement of overall outcome 45-47 . In one nonrandomized study, where more than 40% of patients received thrombolytic therapy, there was improved survival rate of 46% in those who received IABP versus 38% in those who did not [P =0.001] 46 . IABP is extremely useful especially in patients in whom support of the circulation is required for the performance of cardiac catheterization and/or other interventional revascularization procedures such as PTCA or CABG. It is mandatory in patients with mechanical complications of AMI such as ventricular septal defect or papillary muscle rupture as a temporary support before surgical correction. Patients 5 treated with IABP in conjunction with thrombolytic therapy had the lowest in- hospital mortality rate (47%) in the SHOCK registry. 48 The SHOCK registry data suggest that initial stabilization of cardiogenic shock patients using an IABP may be associated with a 20% absolute risk reduction in mortality. 48 Similarly, retrospective analysis from the United States National Registry of Myocardial Infarction 5 has shown a 6% absolute reduction in hospital mortality associated with IABP use among cardiogenic shock patients. IABP was recommended in the SHOCK Trial protocol and used in 87% of patients, for a median duration of approximately 3 days. Overall, IABP usage was not an independent predictor of mortality at 12 months; however, in patients who had systemic hypoperfusion and whose hemodynamics and end-organ perfusion were improved by IABP, the mortality rates were lower at 12 months in both the initial medical stabilization and the ERV treatment groups 49 . According to accumulated data and accepted guidelines, all patients having cardiogenic shock without contraindications should receive IABP for at least 3 days or longer if clinically indicated, for recovery from myocardial stunning. 30,31
Other types of mechanical devices that are currently used to provide circulatory support: Ventricular assist device 50 , percutaneous cardiopulmonary by-pass with extracorporeal membrane oxygenation (ECMO) 51 and hemopump 52 . All have been successfully used in a limited number of patients as temporary support before interventions or as a bridge to heart transplantation 53 . Left ventricular assist devices were described in a few retrospective single-center based studies as a promising modality in the post- myocardial infarction setting 54,55 . Anecdotal case reports and case series were published recently confirming the emerging role of urgent cardiac resynchronization therapy (CRT) in inotropes-dependent patients 56-58 .
Thrombolysis There are few randomized trials providing data for assessment of the efficacy of thrombolysis in patients presenting with CS. Intracoronary streptokinase results in low patency rates of only 43% for patients in CS 59 . When reperfusion is established, the mortality rate is significantly lower than when intracoronary streptokinase fails to establish reperfusion, 42% vs 84%, respectively 60 . GISSI I is the only placebo- controlled thrombolytic trial that assessed mortality rates for patients who presented in CS. Streptokinase alone without adjunctive aspirin or anticoagulation administered up to 12 hours after onset (regardless of ECG findings) resulted in the same mortality rate as the placebo (70%). 61 The FTT group emphasized that the possibility of saving seven lives in every 100 patients treated represents a large absolute benefit. 62 The more recent GUSTO I and TIMI II trials, which utilized more adjunctive anti-coagulation reported mortality rates of 58% and 51% at 30 days and 6 weeks, respectively. 63,64 The lack of apparent benefit of thrombolytic agents in the treatment of cardiogenic shock may be the result of reduced lysis of thrombi in patients who have low perfusion pressures 59 . Data from small nonrandomized retrospective studies of patients with shock complicating AMI support the use of IABP in conjunction with thrombolysis 45-47 .
Glycoprotein IIb/IIIa Receptor Antagonists The available data favor administration of platelet IIb/IIIa antagonists, particularly Abciximab, in patients who have cardiogenic shock who 6 are undergoing percutaneous intervention, unless the risk of bleeding is considered to be excessive. In the recently published trial 65 , 40 patients who had ST-segment elevation myocardial infarction and cardiogenic shock were treated with primary revascularization, abciximab, heparin, and aspirin. The reported mortality rate at 30 days was 42.5%. Abciximab seemed to improve outcomes of the younger population [<75 years) versus elderly (>75 years), with mortality rates of 24% versus 91%, respectively (P<001) 65 . Also in those patients presenting with NSTEMI with shock GP IIb/IIIa inhibitors should be administered before revascularization. Other experimental agents like N- Monomethyl-L-Arginine 66 , Tilarginine Acetate Injection 67 Complement blocking agents like Pexelizumab 68-70 , adenosine 71 , Sodium/hydrogen-exchange inhibitors. 72,73 , Antioxidants like Recombinant human superoxide dismutase (h-SOD) 74,75 , Glucose-insulin-potassium infusion 76,77 did not demonstrate any benefit in terms of reduction in serious adverse outcomes.
Revascularization Bypass surgery Early studies of revascularization for patients with cardiogenic shock focused on surgical revascularization. Several small surgical series reported relatively good outcomes in patients who had cardiogenic shock 78,79 . According to SHOCK trial data, surgically revascularized patients benefited mostly among 57 patients who underwent bypass surgery, 30-m day mortality was 42.1%, versus 45.3% for those treated with PCI. The trial was not designed to compare percutaneous and surgical revascularization strategies 26 . There are several surgical techniques designed to optimize outcomes for patients in cardiogenic shock: the use of warm blood cardioplegia enriched with glutamate and aspartate, grafting of large areas of viable myocardium first followed by treatment of infarct-related artery last, and preference of saphenous vein grafts for their high initial flow rates and because they can be rapidly harvested 14 . Pooled data from 25 non-randomized studies involving 391 patients in cardiogenic shock who underwent CABG revealed a 35% in- hospital mortality rate 80 , and is the lowest mortality rate reported for CS in AMI. It is possible that complete revascularization achieved by CABG in this population is the best therapy. Hence it is reasonable to consider urgent CABG with IABP support for CS patients if logistics permit in a given setup.
Percutaneous Transluminal Coronary Angioplasty An important advance in the management of CS complicating AMI is the use of PTCA, which is a highly effective method of restoring perfusion in the infarct related artery. There are currently 22 published studies with an aggregate of 646 patients who underwent PTCA at some time during their hospitalization for CS and AMI. The pooled in-hospital mortality is 45% 80 , which is lower than the historic control mortality rate of 80%. When PTCA is successful the mortality rates are significantly lower than when it is not (33 vs 81%). In the GUSTO 1 trial, patients in cardiogenic shock who were subjected to angiography and PTCA performed within the first 24 hours had a mortality rate of 38%, while the remaining patients had a 62% mortality rate at 30 days 81 . Two prospective randomized trials evaluated the role of revascularization among patients who had cardiogenic shock. The SMASH trial (Swiss Multicenter trial of Angioplasty for Shock) involved 55 patients who had AMI complicated by cardiogenic shock. They were randomized to undergo revascularization (surgical or percutaneous) versus medical therapy alone 34 . SMASH was discontinued 7 prematurely due to low enrolment and physician perception that revascularization was beneficial. In this small study, a 9% absolute reduction in 30-day mortality was seen among patients treated with revascularization (69% versus 78%). This, however, did not achieve statistical significance. The most important randomized study in this context is the SHOCK trial. In this study patients who developed cardiogenic shock within the first 36 hours of AMI (either ST-segment elevation, or new left bundle-branch block) were eligible for enrolment; patients who had mechanical causes for shock or predominantly right-ventricular infarction were excluded 26,82 . In this study an aggressive, invasive approach (angioplasty or coronary artery bypass surgery: emergency revascularization [ERV], generally with IABP) was compared with medical treatment, initial medical stabilization (IMS), including thrombolytic therapy and IABP. Randomization was required within 12 hours of shock onset. Most patients randomized to the ERV (n = 152) underwent coronary angiography (97%), and 87% underwent revascularization (surgical or percutaneous). The primary end point of the study was 30-day mortality. In the ERV arm, the mortality was 46.7%, as compared with 56.0% in the conservative arm. The mortality difference at 6 months achieved statistical significance, and was lower in the ERV group (50.3% versus 63.1%) . The survival curves continued to diverge at 12 months of follow-up 82 . In a prespecified subgroup analysis, the benefits of ERV were seen only in patients younger than 75 years of age, in whom the 30-day mortality was 56.8% for the conservative arm versus 41.4% for the ERV arm, however, 30-day survival among medically treated patients older than 75 years tended to be better than that of older patients in the ERV arm (53.1% versus 75.0%). 14 The 13% absolute reduction in mortality at 6 months associated with the aggressive revascularization strategy (50.3% versus 63.1%) was both statistically and clinically significant. On the basis of the SHOCK trial, the American College of Cardiology/American Heart Association (ACC/ AHA) guidelines for the treatment of patients who have myocardial infarction have included early revascularization for shock as a Class I indication, particularly for those less than 75 years of age 30 In the Global Registry of Acute Coronary Events (GRACE) study, percutaneous revascularization with coronary stenting was the most powerful predictor of hospital survival among shock patients. 83
CONCLUSION Cardiogenic shock continues to remain a challenge for the cardiologist taking care of patients of acute myocardial infarction. Based on the data presented above, one should adopt an aggressive approach with emergency PCI with IABP for these critically sick patients. Stenting supported by IIb/IIIa blockers has to be part of the interventional approach.
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Fig 1
Fig 1. Current concept of CS pathophysiology. The classic description of CS pathogenesis is shown in black. Myocardial injury causes systolic and diastolic dysfunction. A decrease in CO leads to a decrease in systemic and coronary perfusion.This exacerbates ischemia and causes cell death in the infarct border zone and the remote zone of myocardium. Inadequate systemic perfusion triggers reflex vasoconstriction, which is usually insufficient. Systemic inflammation may play a role in limiting the peripheral vascular compensatory response and may contribute to myocardial dysfunction.Whether inflammation plays a causal role or is only an epiphenomenon remains unclear. Revascularization leads to relief of ischemia. It has not been possible to demonstrate an increase in CO or LVEF as the mechanism of benefit of 12 revascularization; however, revascularization does significantly increase the likelihood of survival with good quality of life. IL-6 indicates interleukin-6; TNF-, tumor necrosis factor-; and LVEDP, LV end-diastolic pressure. Adapted from Hochman 21 and Hollenberg et al 15 with permission of the publishers. Copyright 2003, the American Heart Association, and copyright 1999, the American College of Physicians.
Fig 2: Kaplan-Meier curve showing 12 month survival in the early revascularization and initial medical stabilization arms of the SHOCK trial. 82
Box 1 Hochman et al proposed criteria for diagnosis of cardiogenic shock as shown in box 1.
Address for correspondence: Dr. K. Sarat Chandra, Additional Professor, Department of Cardiology Nizams Institute of Medical Sciences, Hyderabad 500 082 13