Management of cardiogenic shock complicating acute myocardial infarction: A review

Despite advances in percutaneous coronary interventions and their widespread use, mortality in patients presenting with acute myocardial infarction (MI) complicated by cardiogenic shock (CS) has remained very high, and treatment options are limited. Limited evidences exist, supporting many of the routinely used therapies in treating these patients. In the present article, we discuss CS complicating MI in general and an update on the currently available treatment options, including inotropes and vasopressor, coronary revascularization, mechanical circulatory support devices, mechanical complications, and long‐term outcomes.


| INTRODUCTION
Cardiogenic shock (CS) continues to be the leading cause of mortality in patients presenting with acute myocardial infarction (AMI), 1 the incidence ranging between 5% and 8%. 2 Although with advances in treatment, mainly early revascularization, the overall mortality in patients presenting with AMI has markedly reduced, but still the mortality in patients presenting with AMI complicated by CS remains very high (ffi50%). 1 Limited evidences exist, supporting many of the routinely used therapies in treating these patients. The purpose of the present article is to highlight and discuss the significance of CS and presently available treatment options.

| DEFINITION
CS is a state of decreased cardiac output resulting in end-organ hypoperfusion in the absence of intravascular hypovolemia. Prior studies defined CS, using the markers of cardiac output and tissue perfusion, obtained either invasively, clinically, or biochemically. 3 However, as per the SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK (SHOCK) trial, CS should be defined as 1 : persistent hypotension (systolic blood pressure <90 mm Hg, or requirement of vasopressor to maintain systolic pressure >90 mm Hg), 2 reduction in cardiac output (CO) (<1.8 L/min/m 2 without support or 2.0 to 2.2 L/min/m 2 with support), in presence of elevated left ventricular end-diastolic pressure (EDP). 3 Clinically, signs of organ hypoperfusion, for example, cold extremities, reduced urine output, and altered mental status in extreme cases are present in these patients, 4 as described in Table 1. Although the staging of shock has not been well defined, higher mortality was noted in patients who required inotropic agents, especially in higher doses. 5 3 | PATHOPHYSIOLOGY Acute deterioration in the left ventricular (LV) contractility is usually the main cause of CS. However, impaired right ventricular (RV) systolic function and deranged vasculature functionality may also contribute toward establishment and/or worsening of CS. Reduced CO affects coronary perfusion, resulting in a downward spiral of impaired myocardial contractility and overall worsening of CS. The presence of obstructive atherosclerotic coronary artery disease may further exacerbate reduced coronary perfusion. Although left ventricular ejection fraction is a prognostic marker in patients presenting with CS, 6 contrary to the general belief, LV systolic function is not always severely impaired. 7 The observed left ventricular ejection fraction in the SHOCK trial was ffi30%, the value commonly noted in many of the trials evaluating heart failure and post-myocardial infarction (MI) therapies. 4,[8][9][10] Not only systolic impairment, but also diastolic dysfunction and associated restrictive filling pattern are common findings in patients presenting with CS. 11 Similarly, isolated RV dysfunction can also result in CS, albeit in a very small number of patients (~5%), whereas in the majority of patients it co-exists with LV dysfunction. 12 RV dysfunction influences LV contractility not only by reducing LV preload, but also by influencing ventricular interdependence or by leftward bowing of the interventricular septum-mediated change in the LV geometry and resultant contractility. 12 In a small proportion of patients, ischemia also affects right atrial function, and results in reduced RV filling. 13 Generally, patients presenting with CS due to RV dysfunction are younger, have less multivessel disease, and are less likely to have a previous history of MI. 14 CS due to predominant RV failure has a similar mortality rate to that due to LV dysfunction. 12 Some of the patients with CS may present with out-of-hospital cardiac arrest that is independently associated with very high inhospital mortality. 15 Coronary artery disease is a major cause of cardiac arrest; either due to its presentation with AMI or ischemia induced ventricular tachyarrhythmias.
Hypoperfusion of vital organs triggers catecholamine and vasopressin release, aiming to improve end-organ perfusion by augmenting myocardial contractility and peripheral vasoconstriction. In the shortterm, such neurohormonal changes improve tissue perfusion.
However, persistently elevated levels have a detrimental effect on myocardial function due to elevated afterload and myocardial oxygen demand, especially in the context of reduced CO and impaired coronary perfusion. In the presence of neurohormonal activation, one would expect the systemic vascular resistance (SVR) to be elevated; the mean SVR in the SHOCK trial was in the normal range, and interestingly, 54/302 (18%) of the study cohort were suspected to have septic shock due to fever, leukocytosis, and significantly lower SVR. 16 Up-regulation of inducible nitric oxide synthase (i-NOS), in response to inflammatory stimuli produces pathological amounts of nitric oxide (NO) that can promote inappropriate vasodilation along with inhibition of myocardial inotropy. Experimental animal studies demonstrated beneficial effects of selective iNOS blockade. 17 Similarly, single-center experience with this non-selective NOS inhibition demonstrated promising results in patients with refractory CS. 18 Whereas, such an approach failed to demonstrate mortality benefit, when compared with placebo in a randomized study. 19 Similarly, elevated levels of other inflammatory markers, such as C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6, and their subsequent change predicted death and occurrence of CS in patients presenting with STEMI. 20 However, inhibiting complement component (C5), a downstream signaling of many inflammatory pathways, with pexelizumab failed to demonstrate beneficial effects either in the development of shock or associated mortality. 21 In addition to ventricular dysfunction, mechanical complications of AMI, such as ventricular septal defect, free wall rupture, papillary muscle rupture can also result in CS. They contributed 12% of CS cases in the SHOCK trial. 22 Although the rate of such complications has reduced since introduction of primary percutaneous coronary intervention (PPCI), 23 their occurrence carries high mortality. Similarly, acute mitral regurgitation, either due to papillary muscle/chordae rupture or poor coaptation due to LV dilatation complicates AMI, resulting in CS. Such mechanical complications should be suspected, especially when patients present in CS with relatively small infarct size. Etiologies resulting in CS are described in Table 2, whereas risk factors associated with establishment of CS are listed in Table 3.

| INITIAL ASSESSMENT
CS is a medical emergency; a high index of suspicion, rapid diagnosis, and immediate commencement of treatment, including transferring patients to a tertiary cardiac center may influence clinical outcomes. 24 Moreover, CS can develop at any time throughout the patient's illness, mainly following arrival to the hospital. 25 History of chest pain and electrocardiographic changes of AMI with signs of CS will confirm the diagnosis. In addition, major non-cardiogenic categories of shock, such   27 In addition, the majority of these patients have elevated RV EDP, and any further increase may have detrimental effects. 4 Although the routine use of right heart catheterization in managing critically ill patients in intensive care has declined, as their use was reported to be associated with higher mortality, and excess resource utilization. 28 However, the Swan-Ganz catheter may play a role in managing patients with predominant RV failure, as the cardiac output is higher (with/without inotropic support), when the RV EDP is between 10 and 15 mm Hg. 29 Alternatively, non-invasively assessed mitral deceleration time of less than 140 ms is predictive of pulmonary capillary wedge pressure of >20 mm Hg. 11 Previously published arti-

| PHARMACOTHERAPY
Aspirin, heparin, and other pharmacotherapeutic agents should be used in accordance with the guidelines in managing patients presenting with AMI, as they are associated with better survival. Although, β-blocker use reduces mortality in patients with AMI, caution should be exerted, as intravenous metoprolol use in the COMMIT trial was associated with increased incidence of CS, especially in first 24 hours from AMI, 31 whereas in the SWEDEHEART registry, it was associated with excess in-hospital CS and 30-day mortality. 32 Systemic hypoperfusion, a characteristic of CS, results in lactic acidosis that inhibits myocardial contractility. The early treatment of CS is aimed at preserving or restoring adequate CO to maintain tissue perfusion.

| Supportive therapy
Administration of oxygen should be reserved for hypoxic patients as supplementary oxygen therapy increases coronary vascular resistance, 33 and there are suggestions that its use in non-hypoxic patient is associated with higher mortality. 34

| Inotropes and vasopressors
Inotropes and vasopressors are used in the management of patients   47 Although, levosimendan is licensed in many countries worldwide; the FDA has not approved its use in the United States yet. Overall, majority of these agents improve myocardial contractility and CO, so that their use over a shorter period in patients with CS can be justified. Evidence supports combining these agents in lower doses, rather than using them at higher doses in isolation.
Mechanisms, doses, and side effects of various agents are described in devices that can offer hemodynamic support, independent of myocardial contractility. 53 In general, MCS can be classified as those to be used for short vs long-term, deployed percutaneously vs surgically, or based upon their mechanisms.

| Intra-aortic balloon pump
For years, the Intra-aortic balloon pump (IABP) served as the mainstay MCS therapy for patients presenting with AMI-CS. IABP augmented coronary and peripheral perfusion, and increasing CO by 0.5 L/min. 54 In the SHOCK trial, patients who demonstrated hemodynamic improvement with IABP use had better survival. 55 However, in a prospective randomized multi-center IABP SHOCK-II study, IABP use failed to demonstrate any benefit, including hemodynamic stabilization, length of stay in the intensive care unit, need for inotropic support, and most importantly, mortality. 56 Evidences supporting use of IABP in AMI-CS patients is very week, as observed in the latest ACC/AHA (class IIa, level of evidence B), 57 and the ESC guidelines (class IIb, level of evidence B).

| Impella
An early attempt at using a catheter-mounted, axial flow device positioned across the aortic valve to offer hemodynamic support in CS patients was performed nearly 20 years ago. 58  to demonstrate a 30-day mortality benefit, and was associated with a higher incidence of hemolysis. 59 In a retrospective multi-center Impella-EURO SHOCK registry of 120 patients, Impella 2.5 use demonstrated improved hemodynamic parameters and better organ perfusion. 60 The USpella registry demonstrated better survival and more complete revascularization in patients presenting in CS, who had an Impella 2.5 implanted pre-PCI. 61 The on-going National CS Initiative will be the seminal trial of this device. Initial data demonstrated improved mortality with Impella over historical data from the SHOCK study. 62 The advantages of the Impella devices are familiar implantation technique (similar to pigtail catheter), and single arterial access. Even though the Impella offers superior hemodynamic performance than the IABP, no mortality benefit has been demonstrated thus far. At the same time, this reliable hemodynamic profile comes at the cost of increased risk of vascular complications. 63,64 The FDA has approved all Impella devices for partial circulatory support for up to 6 hours.

| TandemHeart
The TandemHeart (CardiacAssist, Inc., Pittsburgh, Pennsylvania) is another peripheral MCS that can provide 3.5 to 4.5 L/min of flow.
The TandemHeart offered superior hemodynamic support than the IABP, but also failed to demonstrate a 30-day mortality benefit. 65 In patients with CS that was refractory to IABP and vasopressor support, deployment of the TandemHeart was associated with rapid improvement in hemodynamic and metabolic parameters. 66 The TandemHeart can also offer hemodynamic support in patients with RV failure. 67 As TandemHeart insertion requires transseptal catheter placement in the left atrium, an operator requires skills to perform a septal puncture. In addition, its use is associated with higher bleeding and ischemic limb complications. 68 The FDA has approved the device for circulatory support for up to 6 hours. Various MCS devices are summarized in  capable of providing circulatory support of up to 5 L/min. The catheter is positioned in the descending aorta, where it works in a series with heart and reduces left ventricular afterload. 69 Safety and efficacy of its use in acutely decompensated heart failure patients has been verified. 70 Similarly, the iVAC 2 L and 3 L (PulseCath BV, Amsterdam, Netherlands) is a 17-21F catheter with an integrated 2-way valve system, capable of offering circulatory support of 2 to 3 L/min. Standard IABP console can also drive an MCS from PulseCath. In addition, this MCS device can also be used as a ventricular assist device (VAD) to support the right ventricle, which requires insertion through the pulmonary artery. 71

| Extracorporeal membrane oxygenation
Although this technology was introduced more than five decades ago, PCI was shown to be an independent predictor of 30-day survival in patients presenting with AMI complicated with profound CS. 74 However, authors stated that patients were enrolled on a contemporary basis and therefore, there may be an impact of non-identical treatment on outcomes in the two groups. 74 Portable ECMO support can be initiated in patients with refractory CS; either in the out-ofhospital setting or in the referring hospital, even in situation of ongoing cardio-pulmonary resuscitation and these patients can be transferred for further care in a tertiary center or to the catheterization laboratory for PCI. 75 In a series of patients treated with ECMO support for CS, 42% survived to hospital discharge. However, 57% of patients suffered ECMO-related major complications, 76   year, annualized death rates were 8.0 and 10.7/100 patient-years in the revascularization and conservative stabilization groups, respectively. 48 Eleven year follow-up data from the US patients, who participated in the Global Utilization of Streptokinase and Tissue-Type Plasminogen Activator for Occluded Coronary Artery (GUSTO)-1 trial, reported 2% to 4% yearly mortality irrespective of their presentation with or without shock. 88 In a prospectively collected registry of patients with AMI-CS, 80% of in-hospital survivors were in New York Heart Association Functional Classification (NYHA) class I/II at a median follow-up of 18.1 months. 89 Increasing age, female sex, baseline renal dysfunction, long-time from symptom onset to revascularization, and thrombolysis in myocardial infarction (TIMI) flow less than 3 at the end of PCI, are factors associated with high mortality in CS patients.
Attempts are made at various front to improve the outcomes in patients with AMI complicated by CS. Recently published articles have proposed the need for team-based approach in managing this patient population; especially establishing advanced cardiac shock care centers. 90,91 In addition to accepted "door-to-balloon time," there is emerging concept of "door-to-support/unloading time" using mechanical circulatory support in patients with AMI-CS. 92 Adopting a regional shock protocol, the "Detroit cardiogenic shock initiative" has demonstrated the feasibility and effectiveness of establishing early mechanical circulatory support in AMI-CS patients. 93 On the contrary, ideal timing of initiating mechanical circulatory support, and its mortality benefit; effectiveness of recently published ORBI risk score in identifying patients at risk of developing CS after presentation with AMI, 94 and effectiveness of therapeutic hypothermia in patients with CS 81 warrants further evaluation.

| CONCLUSION
With early revascularization, the frequency of CS complicating AMI, and resultant mortality have reduced, albeit overall mortality still remains very high, and treatment options are limited. Early diagnosis and institution of therapy to break the vicious circle of LV dysfunction, and resultant coronary/tissue hypoperfusion are of paramount importance. Although MCS/VADs significantly improve hemodynamic parameters and end-organ perfusion in patients with CS, till date such support devices have failed to demonstrate mortality benefit. There is clearly a need for further randomized trials to assess newer drugs, support devices, and treatment strategies.