Percutaneous interventional cardiovascular medicine

Summary

Cardiogenic shock is a high-acuity, potentially complex, and hemodynamically diverse state of end-organ hypoperfusion which is frequently associated with multisystem organ failure. CS complicating acute myocardial infarction (AMI) remains common and is associated with high mortality.

The presence of ischaemic myocardium has a profound impact on the initial, in-hospital, and post-discharge management and prognosis of the cardiogenic shock patient. Careful risk assessment for each patient, based on clinical criteria, informs decisions regarding aggressive therapeutic interventions, triage among alternative hospital care levels, and allocation of clinical resources.

This chapter will outline the underlying causes and diagnostic criteria, the pathophysiology and treatment of cardiogenic shock complicating AMI, including mechanical complications and shock from right heart failure.

There will be a major focus on potential therapeutic angles from the perspective of the interventional cardiologist and also the intensive care perspective on advancement of circulatory support and pharmacological support. Since studying the cardiogenic shock population in randomised trials remains challenging, we will also touch on the specific challenges encountered in previous clinical trials and the implications for future perspectives in cardiogenic shock.

Introduction

The incidence of cardiogenic shock in patients with AMI differs depending on the definition of cardiogenic shock, but it has been estimated to range from 5% to 15% with some decline in the last years.[1, 2, 3, 4, 5]

Assuming a five to eight per cent incidence of cardiogenic shock of all hospitalised AMI, this translates in approximately 60,000 to 70,000 cases per year in Europe. Numerous clinical complications are associated with the development of AMI, but none are more potentially devastating or carry a worse prognosis than cardiogenic shock.

While the mortality of patients with AMI was reduced from 30% to 5% and less for non-cardiogenic shock patients during recent decades, in the subgroup of patients with cardiogenic shock, improvements were much less impressive [6, 7, 8].

Despite advances in myocardial reperfusion therapy over the last two decades leading to a steady reduction in mortality rates, remains the leading cause of death with hospital mortality rates still approaching 50% [9, 10, 11].

Major efforts are needed and also intensified research should be directed to improve the prognosis of cardiogenic shock patients.

Definition and diagnosis

DEFINITION

Cardiogenic shock of every cause is a state of impaired end-organ perfusion due to a reduced cardiac output. It is characterised by hypotension, pulmonary congestion and impaired tissue and vital organ perfusion. In general, cardiogenic shock can be clinically defined. However, in particular in clinical trials, additional haemodynamic parameters such as the assessment of left ventricular (LV) filling pressures or the cardiac index were also used to define cardiogenic shock [10, 11].

FOCUS BOX 1Criteria for cardiogenic shock definition

Systolic blood pressure < 90 mmHg lasting >30 minutes (in the absence of hypovolaemia) or vasopressors required to achieve a systolic blood pressure ≥90 mmHg
Pulmonary congestion or elevated left ventricular filling pressures (pulmonary capillary wedge pressure >18 mmHg)
Signs of impaired organ perfusion with at least one of the following criteria
a) Altered mental status
b) Cold, clammy skin and extremities
c) Oliguria with urine output <30 ml/h
d) Serum-lactate > 2.0 mmol/l
Reduction of cardiac index (<1.8 l/min/m² without and 2.0-2.2 l/min/m² with support) (optional)

The Society for Cardiovascular Angiography and Interventions (SCAI) has recently proposed a new definition of cardiogenic shock, including five categories of (a) at risk, (b) beginning or pre-shock, (c) classical, (d) doom, and (e) extremis cardiogenic shock.[21] Hemodynamic abnormalities form a spectrum that ranges from mild hypo-perfusion to profound shock, and the short-term outcome is directly related to the severity of hemodynamic derangement [12, 13]. Pre-shock is defined as clinical evidence of relative hypotension or tachycardia without hypoperfusion [12]. Such patients should be monitored closely and treated early to avoid development of classical cardiogenic shock. Extremis cardiogenic shock includes cases in which considerations about the futility of treatment should be carried out and possibly palliative care initiated [12].

DIAGNOSIS

The diagnosis of vital organ hypoperfusion may be manifest clinically by

cool extremities due to centralisation of blood volume
decreased urine output (usually < 30 ml/h) and/or
alteration in mental status.

In addition, serum lactate measurements may be used for the assessment of impaired peripheral microcirculation [14, 15]. Serum lactate has the advantage of the ability to assess even subtle changes in the peripheral microcirculation at a very early stage before clinical signs become evident. Elevated arterial lactic acid levels are non-specifically indicative of tissue hypoxia but are associated with mortality in cardiogenic shock [16, 17]. The pathogenesis of lactate production in cardiogenic shock is uncertain, although impaired oxygen delivery, stress-induced hyperlactatemia, and impaired clearance are likely contributors [18].

Acute kidney injury, which is reflected by a rise in serum creatinine and a potential reduction in urinary output, in the setting of cardiogenic shock may indicate renal hypoperfusion and is associated with poor outcomes [19]. Novel renal biomarkers such as neutrophil gelatinase–associated lipocalcin, kidney injury molecule 1, and cystatin C were not more effective than standard evaluation with serum creatinine for assessing risk and prognosis [19].

The assessment of LV filling pressures or the cardiac index usually requires the use of pulmonary artery catheterisation (PAC). However, cardiogenic shock diagnosis does not necessarily need invasive measurements, and this may also delay treatment of cardiogenic shock. Doppler echocardiography may also be used to confirm elevation of LV filling pressures but in clinical practice it can also be diagnosed clinically by simple blood pressure assessment in conjunction with clinical signs of pulmonary congestion and end-organ hypoperfusion [9, 20].

Special situations apply for cardiogenic shock patients with right heart failure, free wall rupture or ventricular septal defect (VSD), or ischaemic acute mitral regurgitation. The underlying cause of shock in these patients can easily be evaluated by echocardiography revealing the LV dysfunction and associated mechanical complications.

A comprehensive transthoracic echocardiography is of paramount importance for the detection of the underlying cause of cardiogenic shock and therefore, should be performed in all patients as early as possible [21]. When images are inadequate or the diagnosis remains uncertain, a transoesophageal echocardiogram should be considered.

The typical haemodynamic situation of patients with classical cardiogenic shock from LV-dysfunction, those with mechanical complications and right heart failure as measured by PAC are shown in Table 1 . Haemodynamic characteristics of cardiogenic shock.

Haemodynamic abnormalities described above represent a spectrum which ranges from mild hypoperfusion to profound shock, and the short-term outcome is directly related to the severity of haemodynamic derangement. However, cardiogenic shock should be diagnosed in all patients exhibiting signs of inadequate tissue perfusion irrespective of blood pressure. Some patients develop signs of end-organ hypoperfusion in the setting of unsupported blood pressure measurements >90 mmHg. This “pre-shock” presentation is also associated with a high risk of in-hospital morbidity and mortality.

The differential diagnosis between CS and other causes of shock (i.e., hypovolaemic, extracardiac obstructive, distributive) is based mainly on history, physical examination, electrocardiogram (ECG), echocardiography and laboratory data.

Causes of cardiogenic shock

Any cause of (acute) severe left or right ventricle dysfunction may lead to cardiogenic shock which can occur acutely in a patient without prior cardiac history or progressively in a patient with long-standing chronic heart failure [22]. ( Table 2)

AMI with subsequent LV-dysfunction remains the most common cause of cardiogenic shock. The incidence of shock after non-ST-elevation myocardial infarction (NSTEMI) seems to be lower than after ST-elevation MI (STEMI) ( Figure 1 ). The median time after AMI onset for occurrence of shock in the randomised “SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK" (SHOCK) trial and the SHOCK registry were 5.0 and 6.0 hours, respectively [9, 23]. Shock complicating unstable angina or NSTEMI seems to occur at a later time period with a median of 76.2 and 94.0 hours, respectively [24].

In general, a loss of >40% of functional myocardium is required to cause cardiogenic shock as shown in autopsy studies [25]. However, mechanical complications such as ventricular septal rupture, free wall rupture, and papillary muscle rupture or dysfunction also contribute to cardiogenic shock after AMI [23].

In addition, any cause of acute and severe LV or right ventricular (RV) dysfunction might also lead to cardiogenic shock. Acute perimyocarditis, the apical ballooning syndrome also called TakoTsubo syndrome, and hypertrophic obstructive cardiomyopathy may all present with ST-segment changes, elevation of cardiac biomarkers, and shock in the absence of significant coronary artery disease. The Takotsubo syndrome is defined by acute transient LV-dysfunction after emotional or physical stress in the absence of significant coronary artery disease and can lead to cardiogenic shock in 4.2% of cases [26, 27, 28]. Acute valvular dysfunction such as acute regurgitation, typically caused by endocarditis or chordal rupture due to trauma or degenerative disease, may also cause shock. Similarly, aortic dissection with acute, severe aortic insufficiency or infarction might lead to cardiogenic shock. Cardiac tamponade or massive pulmonary embolism can present as cardiogenic shock without associated pulmonary congestion.

FOCUS BOX 2Causes of cardiogenic shock

Acute myocardial infarction (>40% loss of functional myocardium)
Mechanical complication of acute myocardial infarction
−−Ventricular septum defect
−−Free wall rupture
−− Acute ischaemic mitral regurgitation (papillary muscular dysfunction)
Acute (peri-) myocarditis
Apical ballooning syndrome
Sustained tachyarrhythmias or bradyarrhythmias
Acute valvular dysfunction
Intracardiac tumours
End-stage cardiomyopathies

Pathophysiology

GENERAL PATHOPHYSIOLOGY

FOCUS BOX 3Mechanisms behind the associations of bleeding/transfusion with mortality

Hypotension
Anaemia
Ineffective oxygen delivery
Vasoconstriction
Platelet dysfunction
Cessation of evidence-based antithrombotic or antiplatelet therapies

This complexity expands the current concept of cardiogenic shock pathophysiology (shown in Figure 2 ) as introduced by Thiele et al [32].

SPECIAL FEATURES IN FREE WALL RUPTURE AND VENTRICULAR SEPTAL DEFECT

In general, the pathophysiology in mechanical complications is similar to the overall pathophysiology in cardiogenic shock.

Rupture of the ventricular free wall, a dramatic clinical event, is an uncommon but not rare cause of death in patients hospitalised with AMI [38]. The overall incidence of this complication is difficult to assess because clinical and autopsy series differ considerably. In some series it was estimated to be about 6%, but it accounted for as much as 15% of the in-hospital mortality after AMI [39]. Late reperfusion, large infarctions, advanced age and female gender are known risk factors for rupture [40]. In addition, these patients usually have less pulmonary oedema, less diabetes, less prior AMI, and less prior congestive heart failure at presentation. No haemodynamic characteristics can identify patients with rupture or tamponade [41].

In many patients free wall rupture is usually associated with sudden profound shock, often leading rapidly to pulseless electrical activity caused by pericardial tamponade. However, others present with a less acute clinical course, which allows for potentially life-saving therapeutic interventions. These patients often present with hypotension and other signs of cardiogenic shock [42, 43].

Rupture of the septum is usually characterised by a new harsh, loud holosystolic murmur that is heard best at the lower left sternal border and which is mostly accompanied by a thrill. The diagnosis can easily be made by echocardiography. Due to the left-to-right shunting there is usually a volume overload of the RV and an obligatory “step-up” in the oxygen saturation between the right atrium and the RV or the pulmonary artery ( Table 1 ). For quantification of the left-to-right shunt, the shunt volume, shunt flow ratio and effective cardiac output can easily be determined by the Fick method using a PAC. The cause of shock is usually a mixture from LV and RV failure due to the volume overload of the RV. Major determinants of the cause of shock are the shunt flow ratio, RV and LV function.

SPECIAL FEATURES IN ACUTE ISCHAEMIC MITRAL REGURGITATION

Acute ischaemic mitral regurgitation can be caused by a several conditions.

FOCUS BOX 4Mechanisms of ischaemic mitral regurgitation

LV global or regional remodelling
Papillary muscle dysfunction (rare)
Papillary muscle rupture (partial or complete)
Acute systolic anterior motion of the mitral valve

The most severe and important is related to partial or total rupture of a papillary muscle which requires immediate treatment. Similar to VSD occurrence these patients manifest a new holosystolic murmur and develop increasingly severe heart failure with lung oedema. In some cases the murmur is only mild and many patients present with a hypercontractile ventricle. The cause of shock can usually easily be determined by echocardiography. In addition, patients with ischaemic mitral regurgitation do not present a “step-up” in oxygen saturation between the right atrium and RV but with a tall v-wave in the pulmonary capillary wedge pressure (PCWP) and also pulmonary artery tracings. Unlike VSD or free wall rupture, papillary muscle rupture occurs relatively often in rather small infarctions. Inferior wall infarctions can lead to rupture of the posteromedial papillary muscle which is much more common than the rather rare rupture of the anterolateral papillary muscle which is usually a consequence of anterolateral infarctions.

SPECIAL FEATURES IN RIGHT HEART FAILURE

Usually, RV ischaemia during AMI is caused by proximal occlusion of the right coronary artery (RCA) leading to depressed RV function and decreased LV preload, resulting in reduced cardiac output despite normal or only mildly reduced LV function [44]. Clinically, these patients are characterised by severe right heart failure, clear lungs, and low output despite intact global or only mildly reduced LV systolic function. Although in general the magnitude of haemodynamic derangements in patients with RV ischaemia is related to the extent of RV free wall contraction abnormalities, some patients tolerate severe RV systolic dysfunction without haemodynamic compromise whereas others develop life-threatening low cardiac output, emphasising that additional factors modulate the clinical expression of RV ischaemia.

An elevated intrapericardial pressure and a paradoxical movement of the interventricular septum towards the volume-depleted LV further limits LV function. In this setting, the loading of both ventricles (circulating volume), interventricular septal function, and the contribution of the right atrium to RV filling (cardiac rhythm) are essential and may be important factors determining the clinical presentation and outcome. Despite significant haemodynamic compromise, arrhythmias, and even increased early mortality, the clinical condition of most patients with acute RV ischaemia improves spontaneously. In general, RV heart failure is characterised by an elevated central venous pressure (CVP) which is usually higher than the PCWP ( Table 1 . Haemodynamic characteristics of cardiogenic shock).

SPECIAL FEATURES UNLOADING THE LEFT VENTRICLE IN ACUTE MYOCARDIAL INFARCTION

pVAD for acute left ventricular unloading may be a useful option in myocardial ischaemia during primary PCI in compromised patients [45]. In acute myocardial infarction, cardiac unloading is used to reduce oxygen demand and possibly limit infarct size. Research has demonstrated the benefits of short-term unloading with mechanical circulatory support devices before reperfusion in the context of acute myocardial infarction with cardiogenic shock, and a confirmatory trial is ongoing [46, 47]. At comparable device flow rates, TandemHeart decreased LV pre-load, native LV stroke volume, and myocardial contractility to a greater degree than Impella. Reductions in load-independent indexes of LV performance indicate favourable effects on myocardial oxygen balance and support further study of TandemHeart in clinical scenarios requiring mechanical support in the setting of acute myocardial ischemia [48]. IABP could not demonstrate an advantage over standard‐of‐care medical treatment in infarct‐related cardiogenic shock in a randomized trial [49].

Risk factors and prognostic factors

Because of the potentially serious consequences of cardiogenic shock, identification of subgroups of patients with acute coronary syndromes who are at high risk of developing shock is important. In the fibrinolytic era, algorithms were developed to predict the occurrence of in-hospital cardiogenic shock among patients with different types of STEMI and NSTEMI.

These algorithms were validated in subsequent trials with a high concordance index, indicating that these algorithms are applicable to both populations of acute coronary syndrome patients [50] [51]. However, more recent validated algorithms in the percutaneous coronary intervention (PCI)-era are not available.

If cardiogenic shock is present, it is also valuable to have prognostic markers to predict outcome. In the fibrinolytic era, a score was developed to predict mortality [52]. Adding variables such as age, height, baseline heart rate and systolic blood pressure, presence of VSD, presence of free wall rupture, prior infarction, prior angina, time to fibrinolysis, infarct location, Killip classification, diabetes, smoking status, altered sensorium, cold and clammy skin, oliguria, and arrhythmia led to a number of points predicting 30-day death, ranging from 10% to 90%.

In the PCI-era, mortality due to cardiogenic shock can still range from 10% to 80% depending on demographic, clinical, and haemodynamic factors. Simple clinical predictors provide good discrimination of mortality risk in CS complicating MI. [53] These factors are similar in comparison to the pre-PCI era and include age, clinical signs of peripheral hypoperfusion, hypoxic brain damage and LV ejection fraction. In addition, initial haemodynamic parameters are predictive of short-term mortality. The strongest haemodynamic predictor is the cardiac power index, which is derived from the product of simultaneously measured cardiac index and the mean arterial blood pressure. By coupling both pressure and flow domains of the cardiovascular system, this provides a measure of cardiac pumping [54]. It is calculated by the cardiac index x mean arterial pressure x 0.0022 and is expressed as Watt/m2. Among cardiogenic shock patients undergoing PCI, time from symptom-onset to PCI, and post-PCI TIMI flow grade are also independent predictors of mortality (Illustrative Case 1 and Moving images 1-3). Other prognostic parameters include admission blood glucose irrespective of diabetes status, creatinine clearance, admission haemoglobin levels, and serum lactate [55, 56, 57, 58]. Typical factors associated with survival in the PCI-era are shown in Focus box 5. Predictors of mortality in cardiogenic shock.

FOCUS BOX 5Predictors of mortality in cardiogenic shock

Increasing age (≥75 years)
Prior infarction
History of hypertension
Signs of systemic hypoperfusion not quickly reversible
Impaired left ventricular ejection fraction (<25%)
Pulmonary capillary wedge pressure ≥25 mmHg
Reduced cardiac power index
Long time from symptom onset to PCI
Post-PCI TIMI I-flow <3
Multivessel disease
High admission blood glucose
Impaired baseline renal function
High serum lactate
APACHE-2 score

More recently the IABP-SHOCK II risk score (score parameters: age >73 years, prior stroke, glucose at admission >10.6 mmol/l (191 mg/dl), creatinine at admission >132.6 μmol/l (1.5 mg/dl), Thrombolysis In Myocardial Infarction flow grade <3 after percutaneous coronary intervention, and arterial blood lactate at admission >5 mmol/l.) was validated for use in daily clinical practice and strongly correlated with mortality in patients with infarct-related CS.[59] The SCAI shock definition has also been validated in multiple retrospective registries [13, 60]. However, prospective validation in internal- and external cohorts is still missing.

Treatment

REVASCULARISATION

Due to its limited efficacy, fibrinolysis is only reserved for patients when PCI is impossible or if there are significant treatment delays in transport for PCI [21].The SHOCK trial is one of the rare adequately powered and most important randomised trials in cardiogenic shock complicating AMI [9]. Although it failed to meet the primary endpoint - reduction of 30-day mortality by an early revascularisation-based management either by PCI or coronary artery bypass grafting (CABG) - (46.7% versus 56.0%, p=0.11), there was a significant mortality reduction at 6 (50.3% versus 63.1%, p=0.027), 12 months (53.3% versus 66.4%, p=0.03) [61],, and long-term follow-up at 6 years (67.2% versus 80.4%, p=0.03) ( Figure 3 )[62]. To save 1 life, <8 patients need to be treated by early revascularisation in comparison to initial medical stabilisation. The Swiss Multicentre trial of Angioplasty for SHock (SMASH) trial, although stopped prematurely due to slow enrolment, showed similar effects with early revascularisation [63].

Since the widespread application of early revascularisation in clinical practice mainly influenced by guideline recommendations [21], numerous registries have confirmed the survival advantage of early revascularisation leading to a subsequent reduction in cardiogenic shock mortality in the young and also in the elderly [1, 2, 3, 4, 5, 11, 64, 65]. However, more efforts are needed to convince clinicians to recognise that benefit exists despite the high associated risk. This is also important for the elderly patients. The apparent lack of benefit for the elderly in the SHOCK trial was probably due to imbalances between groups. Several subsequent studies including the SHOCK registry, have shown a consistent benefit of revascularisation in elderly patients. This suggests that clinicians are capable of identifying those older patients who are appropriate for revascularisation.

Timing of revascularisation

There is convincing evidence that earlier revascularisation leads to more myocardial salvage in STEMI patients which has a strong prognostic impact [28]. The prevention of shock by early revascularisation is therefore the most effective management strategy. [66] Because in-hospital development of shock often follows no-reperfusion, failed thrombolysis or successful thrombolysis followed by reinfarction a primary PCI strategy is able to reduce the incidence of in-hospital cardiogenic shock, as shown in a Swiss registry [67].

Similarly, to infarctions without shock, earlier revascularisation improves survival in cardiogenic shock. Presentation zero to six hours after symptom onset was associated with the lowest mortality among cardiogenic shock patients undergoing primary PCI in the Arbeitsgemeinschaft Leitende Kardiologische Krankenhausarzte (ALKK) registry, in which door-to-angiography times were <90 minutes in approximately three-quarters of patients [68]. In the SHOCK trial, there appeared to be increasing long-term mortality as time to revascularisation increased from zero to eight hours [62].eight hours [50]. However, there is a survival benefit as long as 48 hours after AMI and 18 hours after shock onset. In a German based registry the time influence of first medical contact to reperfusion on mortality could recently be confirmed [66].

Therefore, the current European Society of Cardiology (ESC) guidelines for revascularisation recommend immediate transfer of all STEMI and NSTE acute coronary syndrome patients for invasive evaluation and target vessel revascularisation (Class 1, Level of Evidence A recommendation) [69]. Immediate reperfusion is also indicated in acute heart failure with ongoing ischaemia (Class 1, Level of Evidence B recommendation) [69].

Therefore, the current European Society of Cardiology (ESC) guidelines for revascularisation recommend immediate transfer of all STEMI and NSTE acute coronary syndrome patients for invasive evaluation and target vessel revascularisation (Class 1, Level of Evidence A recommendation) [56]. Immediate reperfusion is also indicated in acute heart failure with ongoing ischaemia (Class 1, Level of Evidence B recommendation) [56].

Revascularization strategy

The vast majority (between 70-80%), of patients who present with AMI-cardiogenic shock have multivessel coronary disease. Until the results of the randomised, multicentre Culprit Lesion Only PCI versus Multivessel PCI in Cardiogenic Shock (CULPRIT-SHOCK) trial, there was a dearth of evidence to guide decision making [11]. However, both the 30-day and 1-year results of this trial clarify that there is significant net clinical benefit, principally driven by a difference in mortality. This was consistent across all subgroups, for culprit only revascularisation at the time of the index procedure. Specifically, the rate of death and renal replacement therapy, as a composite endpoint, in the culprit-lesion-only PCI group was 45.9%, compared to 55.4% in the multivessel PCI group (relative risk, 0.83; 95%CI 0.71-0.96; p=0.01) including a significant mortality reduction. Importantly, the majority of surviving patients in CULPRIT-SHOCK underwent staged protocol-recommended revascularisation during follow-up in the initial culprit-lesion-only PCI group. Thus, the preferred revascularisation strategy is culprit lesion PCI with subsequent staged revascularisation after clinical stabilisation similar to the ST-elevation myocardial infarction (STEMI) setting without CS.

Percutaneous coronary intervention versus bypass surgery

Theoretically, revascularisation type might have some influence on outcome, similar to stable coronary artery disease [70]. [70]. In observational studies comparing PCI versus CABG, the type of revascularization did not appear to influence the outcome of CS patients [71, 72]. Currently PCI is the most widely available and most often performed revascularization therapy in CS, while CABG is rarely performed with only 4% of patients undergoing immediate CABG in the IABP-SHOCK II-trial and registry which might represent current clinical practice [49]. More than 70% of CS patients present with multivessel coronary artery disease and/or left main disease, which is associated with a higher mortality compared to patients with single vessel disease (Illustrative Case 2 and Moving images 4-6)[73]. In cases of complex coronary anatomy or mechanical complications, the Heart Team should be consulted promptly [21].

PCI is surely reserved for those patients with single or double vessel disease ( Figure 4 ). In multivessel disease, a culprit-lesion-only strategy (with possible stage revascularization of additional lesions) is recommended. [11, 74] CABG may be preferred in complex anatomy, especially when complete revascularisation with PCI is not possible.[69]

A potential revascularisation treatment algorithm for the cardiogenic shock subset is depicted in Figure 4 .

Stent type and thrombectomy for PCI

Regarding the type of stent used if PCI is performed, any difference with respect to hard outcome variables is not assumed for the shock subset. All the evidence reported so far for patients with STEMI without cardiogenic shock, as well as for stable coronary artery disease, has not found a difference in mortality for the use of drug-eluting or bare metal stents.

The only difference was found for repeat revascularisation due to in-stent restenosis [75, 76, 77]. Most recent data from the IABP-SHOCK trial indicate a safe use of drug-eluting stents in the cardiogenic shock setting with similar mortality data at 12-month follow-up [78].

Also, in relation to thrombectomy there are no specific trials in the cardiogenic shock subset and usually these patients were excluded from randomised clinical trials evaluating the benefit of thrombectomy in STEMI [79, 80, 81]. Similar to the large randomised trials in ST-elevation AMI without cardiogenic shock current evidence does not support the use of manual thrombectomy in the shock situation [82, 83, 84]. If some subgroups with massive thrombus or no-reflow after PCI may benefit from aspiration thrombectomy requires further studies as well as specific studies in the cardiogenic

shock subset [84].

Transradial versus transfemoral approach

In hemodynamically stable AMI patients, randomised data demonstrated superiority of transradial versus transfemoral access [85, 86, 87]. In CS, the benefit of transradial access is uncertain and has only been retrospectively investigated in registries and one small subanalysis of RIFLE-STEACS trial [88]. Theoretically, the reduction of all-cause mortality driven by significant reduction of bleeding could also translate in improved prognosis in CS patients. A meta-analysis analyzing data of 8,131 patients demonstrated that transradial access was associated with a reduction in all-cause mortality as well as major adverse cardiac and cerebral events at 30-day follow-up in CS patients. The mechanisms behind this potentially improved outcome following transradial access have not been fully elucidated yet. Most likely, bleeding-related hemodynamic instability and other adverse influences such as blood transfusion–related oxidative stress may be especially critical in CS patients. Further, due to a lower rate of access site bleeding, patients undergoing transradial access could be more likely to receive aggressive antithrombotic therapy such as glycoprotein IIb/IIIa inhibitors. In general, in patients with palpable radial pulse the transradial access appears to be at least feasible. Radial access site may thus be used by experienced interventionalists in the shock setting. However, the radial route poses many potentially time-consuming technical challenges and the catheterization team should be prepared for a quick cross-over to transfemoral access in case of difficulties. Operators without extensive experience in transradial access are well advised to stick to a familiar (usually femoral) access or at least have a low threshold for crossover to a femoral approach.

Anticoagulation and antiplatelet therapy during revascularisation

There are limited data to support the use of antiplatelet agents, including aspirin, in the setting of CS, and data are largely inferred from more stable MI populations.

The SHOCK and also the SMASH randomised trials were performed before pharmacological strategies such as loading with thienopyridines and glycoprotein IIb/IIIa-inhibitors were commonly used. It is well known that early reperfusion by primary PCI and reperfusion success measured by TIMI-flow are major factors which are strongly associated with mortality in cardiogenic shock [68]. Efforts are therefore necessary to improve the reperfusion success.

Antithrombotic therapy with aspirin and heparin should be given as routinely recommended [21, 69].

Clopidogrel, prasugrel or ticagrelor when available may be deferred, because on the basis of angiographic findings, CABG may be necessary immediately. Clopidogrel/prasugrel/ticagrelor is indicated in all patients undergoing PCI, and on the basis of extrapolation of data from AMI patients not in cardiogenic shock, it should also be useful in patients with cardiogenic shock [21]. In a secondary analysis of the IABP-SHOCK II trial, there was no difference in mortality or bleeding events in a comparison of clopidogrel, prasugrel, and ticagrelor in patients with acute MI complicated by CS [89].

Because many patients are intubated and ventilated oral antiplatelets need to be administered using a nasogastric tube or sublingual. Crushing ticagrelor may even be more advantageous based on improved pharmacodynamic properties [69, 90]. Of interest, in the Fabolous-Faster trial, chewed prasugrel, which led to higher active metabolite concentration, but not greater IPA compared with integral prasugrel [91].

Furthermore, cardiogenic shock patients are often intubated and mechanically ventilated and have impaired oral drug absorption leading to delayed onset of action of oral antiplatelet drugs. Observational data support a potential mortality benefit by the use of glycoprotein IIb/IIIa-inhibitors in cardiogenic shock ( Figure 5 )[92, 93, 94]. However, in this specific shock setting, there is only one small, potentially underpowered, randomised trial in 80 patients (with 35% cross-over in the standard treatment group) which failed to confirm that routine upstream abciximab use is superior in comparison to standard treatment with abciximab use according to the discretion of the interventionalist [95]. The primary endpoint (death/reinfarction/stroke/new renal failure) occurred in 42.5% in the up-stream abciximab-group and 27.5% in the standard treatment group (p=0.24) and also in-hospital mortality did not differ (37.5% vs. 32.5%, p=0.82; Figure 5 ) [95]. Given the potential higher bleeding risk with the use of these potent platelet inhibitors the current role in cardiogenic shock cannot be finally determined without adequately powered clinical trials.

Cangrelor may also have advantaged in the cardiogenic shock setting. However, cardiogenic shock patients were excluded from the PLATFORM trials. In the Fabolous-Faster trial, IV Cangrelor provided inferior IPA compared with IV tirofiban [91].

Unfractionated heparin is a commonly used anticoagulant in MI and CS, yet little is known about the appropriate anticoagulant agent for this population. Low-molecular-weight heparin and fondaparinux in the post-PCI setting may be less ideal because of the high prevalence of acute kidney injury in CS. The routine uses of bivalirudin in either stable ST-elevation AMI as well as in the cardiogenic shock setting is no longer recommended. [91, 91, 91, 91].

Given the strong influence of both AMI and major bleeding on subsequent risk of death in AMI and PCI, the optimal antithrombotic regimen would effectively suppress ischaemic complications while minimising iatrogenic haemorrhagic risk.

ADJUNCTIVE MEDICAL TREATMENT

Catecholamines

Irrespective of the underlying cause of cardiogenic shock, the treatment includes initial stabilisation with volume expansion to obtain optimal filling pressures, vasopressors and inotropes plus additional therapy for multiorgan system dysfunction.

Fluid administration in shock is mainly based on pathophysiological considerations and has not been studied in adequate randomised clinical trials. The same applies to catecholamines. The pathophysiological considerations are based on the observation that ischaemic (stunned) myocardium or also hibernating myocardium requires time until functional recovery after revascularisation ( Figure 6 ) [99]. This time to recovery should be bridged by inotropic and also vasopressor support.

Similarly, to fluid administration, the choice of vasopressor and inotropic therapy is mainly based on individual experience. In a randomised clinical trial in 1,679 patients with shock, including 280 cardiogenic shock patients, treatment with dopamine in comparison to norepinephrine was associated with significantly more adverse effects - mainly arrhythmic events - for the overall study cohort and the predefined cardiogenic shock subgroup experienced higher death rates with dopamine ( Figure 7 )[100]. Therefore, when blood pressure is low norepinephrine should be the first vasopressor choice due to its ability to act as a vasoconstrictor with less potential for tachycardia. It should be titrated until the systolic arterial pressure rises to at least 80 mmHg. Subsequently, intravenous dobutamine due to its β2-adrenergic effects may be given simultaneously in an attempt to improve cardiac contractility. Recent heart failure guidelines recommend that vasopressors (norepinephrine preferably) may be considered in patients who have cardiogenic shock, despite treatment with another inotrope, to increase blood pressure and vital organ perfusion [101]. The mode of action of different inotropes and vasopressors used for cardiogenic shock is shown in Table 3 .

Despite the favourable haemodynamic effects of all catecholamines, none have produced consistent improvement in symptoms and many have shortened the survival [102]. These findings may be related to the fact that these agents increase myocardial oxygen consumption and also the concentrations of cAMP, producing an increase in intracellular calcium which possibly leads to myocardial cell death and/or increases lethal arrhythmias [103]. As a consequence, catecholamines should be used in the lowest possible doses. To overcome these problems inherent with catecholamines, in recent years there has been increasing interest in pharmacological agents acting on contractility without the drawbacks of catecholamines.

Levosimendan

Levosimendan is a calcium sensitiser and K-ATP channel opener which improves myocardial contractility. It might be an ideal agent in cardiogenic shock because in comparison to other inodilators, it improves myocardial contractility without increasing oxygen requirements and induces peripheral and coronary vasodilatation with a potential anti-stunning and anti-ischaemic effect. The use of levosimendan and its clinical evidence in different clinical settings has been reviewed in more detail previously [104]. Initial beneficial effects in small trials did not translate into a survival benefit in large-scale clinical trials [104]. Although levosimendan is one of the best studied inotropic agents in acute heart failure, the clinical evidence in cardiogenic shock is very limited. In view of its vasodilatory effects with subsequent blood pressure lowering, it was not a drug of first choice in shock. There are, however, some clinical observations indicating that levosimendan can improve haemodynamics in cardiogenic shock when combined with catecholamines to maintain adequate perfusion pressures, however without apparent mortality benefit [104, 105]. Its current role in cardiogenic shock needs to be defined in further studies. However, to the best of our knowledge, there are no ongoing large-scale clinical trials assessing the clinical benefit of levosimendan in shock patients.

In a recent large-scale randomised trial in septic shock comparing levosimendan versus placebo there was no effect of levosimendan on severe organ dysfunction and mortality. However, there was a lower likelihood of successful weaning from mechanical ventilation [106]. This may influence the believe in this drug also in the CS setting.

Anti-inflammatory agents

Pathophysiological observations that increased levels of nitric oxide (NO) in cardiogenic shock lead to inappropriate systemic vasodilatation, progressive systemic and coronary hypoperfusion, and also myocardial depression led to a small randomised clinical trial demonstrating improved haemodynamics by the administration of NO synthase inhibitors. This also resulted in a survival benefit in a small trial which was halted after 30 patients [107]. Thereafter, based on the dose-ranging SHOCK-2 study, the TRIUMPH trial (Tilarginine Acetate Injection in a Randomized International Study in Unstable MI Patients With Cardiogenic Shock), the largest study in cardiogenic shock to date, investigated if tilarginine improves cardiogenic shock survival. Despite an immediate increase in blood pressure, nitric oxide synthase inhibition did not result in a survival benefit. This led to discontinuation of the trial after inclusion of 398 patients based on a pre-specified interim analysis. The results of the current evidence for NO synthase inhibition and of several other relevant randomised trials performed in cardiogenic shock are displayed in Figure 8 .

Adjunctive monitoring and treatment

Haemodynamic management

Pulmonary artery catheters (PAC’s)(Swan-Ganz catheters) are frequently used in heart failure to confirm the diagnosis of cardiogenic shock, to ensure that filling pressures are adequate, to obtain mixed venous saturation (S_vO₂, see below) samples, and to guide changes in therapy. The best use of this technique is to establish the relationship of filling pressures to cardiac output in the individual patient and additional clinical assessment of responses.

Haemodynamic data derived from PAC measurements, particularly cardiac power and stroke work index, have powerful short-term prognostic value [54]. In recent years, there has been a decline in PAC use relating to controversy regarding the benefit as shown in a meta-analysis [108]. No such association has been shown in CS. [109] Individualised PAC use is now recommended for monitoring of haemodynamic variables or to monitor treatment in patients with severe heart failure not responding to appropriate treatment [21].

Clinical assessment with echocardiography is also a reasonable alternative: Both the pulmonary artery systolic pressure and PCWP can be accurately estimated with Doppler echocardiography, and in particular, the finding of a short mitral deceleration time (<140 ms) is highly predictive of PCWP >20 mm Hg in cardiogenic shock [110].

Fluid responsiveness is a dynamic parameter that may be defined as the change in cardiac output (CO) in response to a change in pressure load. [9] This can easily be ascertained by the administration of a fluid challenge (fixed amount of fluid in a certain amount of time: 100ml of colloids over 10’ e.g.) while monitoring filling pressures atrial pressure (AP), central venous pressure (CVP), heart rate, and cardiac output. On the ascending limb of the Frank-Starling starling ventricular function curve, increasing preload will result in an increase of CO, conversely on the plateau phase vigorous fluid resuscitation may cause pulmonary edema and/or right ventricular dysfunction with no improvement in CO.

Mixed venous oxygen saturation (SVO₂= S_aO₂-VO₂/(CO*Hb*13.9) (S_aO₂ denotes percentage saturation of Hb with oxygen; VO₂ is the amount of oxygen consumed by the body; Hb, haemoglobin concentration in grams per 100 ml blood) has been shown to be a surrogate for the cardiac index as a target for hemodynamic therapy. In cases in which the insertion of a pulmonary-artery catheter is impractical, venous oxygen saturation (central venous oxygen saturation, ScvO₂) can be measured in the central circulation (ScvO₂). [111] Importantly, ScvO₂represents just an approximation of the SvO₂and the absolute values of ScvO₂and SvO₂are not interchangeable. [111] ScvO₂should not be used in isolation in haemodynamic assessment but be used in conjunction with other indicators of organ perfusion such as mental status, urine output and serum lactate levels. Repeated assessments of plasma lactate, for instance, can be informative with respect to the persistence of shock and has been shown to be prognostically important in patients with CS.[112]

A consensus document gives recommendation on the use of haemodynamic monitoring in circulatory shock [113].

Glucose control

Patients in cardiogenic shock as well as other patients in intensive care medicine often develop hyperglycaemia as a result of a relative insulin-resistance and accelerated glucose production. It is also well known that the glucose level at admission is a strong independent predictor for mortality in patients without the previous diagnosis of diabetes mellitus [56]. Based on a previous single centre trial in surgical intensive care patients showing a mortality decrease in patients with intensive insulin treatment this has been adopted at many intensive care units . However, the recent Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation (NICE-SUGAR) trial showed a mortality increase in patients with intensive insulin treatment which is presumably caused by a higher rate of hypoglycemia [114]. Therefore, hypoglycemia must be avoided in patients with cardiogenic shock and a moderate glucose control (≤180 mg/dl or 10.0 mmol/l) should be aimed for.

PERCUTANEOUS MECHANICAL SUPPORT

Different options for percutaneous mechanical circulatory support (pMCS) are available to the medical community (see chapter Percutaneous ventricular assistance).

Systems for temporary MCS vary from simple to highly complex systems[115, 116, 117].

The different modalities of blood flow generation distinguish themselves in terms of the insertion technique (i.e., surgical vs. percutaneous), the sites where blood is withdrawn and returned to the body, flow capacities, and pumping mechanisms. A drawing with mode of operation and technical features of current mechanical circulatory support devices is shown in Figure 10.

Currently, temporary support is directed towards maintaining adequate systemic tissue perfusion, while also favourably impacting myocardial oxygen supply and demand, to optimise myocardial recovery in the face of CS. There is experimental evidence that unloading of the left ventricle (LV) can significantly reduce infarct size and influence myocardial remodeling after an AMI [46].

Mechanical circulatory support (MCS) other than the IABP can be offered at tertiary care centres with an institutional policy for mechanical assist therapy if the patient cannot achieve stabilisation. These LV assist devices (LVAD) have been used in patients not responding to standard treatment including inotropes, fluids and IABP, and also as first line treatment. However, the current experience and evidence is still limited.

Intra-aortic balloon pump (IABP)

The intra-aortic balloon counter-pulsation device (IABP) is one of the most versatile support devices used in the management of patients suffering from the complications of acute cardiovascular disease. Made of a polyurethane membrane mounted on a vascular 7F to 8F catheter, the IABP is positioned in the descending thoracic aorta just distal to the left subclavian artery. Its action is based on the concept of counter-pulsation with the assumption that the reduction in end-diastolic pressure improves the left ventricular function ( Figure 11).

The main limitations of IABP include the lack of active cardiac support, the need for accurate synchronisation with the cardiac cycle, the requirement of a certain level of left ventricle (LV) function, and the limit of support provided [118]. The reduction of left ventricular afterload may be particular helpful in patients with acute mitral valve insufficiency or ventricular septum defect. Absolute contra-indications for IAB pumping include severe aortic valve insufficiency, (acute) aortic dissection. The presence of an aortic aneurysm, severe iliofemoral vascular disease and history of aortic surgery are relative contraindications.

Today, routine use of IABP in CS-patients is no longer indicated [21, 49, 119]. However, IABP may be considered in patients with CS with mechanical complications (i.e. acute mitral regurgitation or a ventricular septal defect) or in case other MCS devices are not available, are contraindicated, or cannot be placed [21]. IABP use rates have subsequently declined [120].

Percutaneous Active Mechanical Circulatory Support devices

Currently established and available percutaneous MCS devices include the TandemHeart (LinaNova, Pittsburgh, PA) and the micro-axial Impella 2.5, CP, and 5.0 systems (Abiomed Europe, Aachen, Germany). Investigational devices include the para-corporeal pulsatile iVAC 2L (PulseCath BV, Arnhem, the Netherlands) and the HeartMate Percutaneous Heart Pump (St. Jude Medical, Pleasanton, CA). Data on percutaneous MCS devices in CS is scarce.[121]. For the iVAC and HeartMate Percutaneous Heart Pump, trial results are not currently available.

Left atrium-to-systemic arterial support (TandemHeart, LivaNova)

The TandemHeart™ removes arterialised blood from the left atrium using a cannula (17 Fr in most patients) placed through the femoral vein and into the left atrium via transseptal puncture. Blood is returned from the left atrium to the lower abdominal aorta (17 Fr femora artery catheter in most patients) or iliac arteries via a femoral artery cannula with retrograde perfusion of the abdominal and thoracic aorta ( Figure 10 ). A more detailed description of the mode of action and implantation procedure has been published earlier [115]. The system is capable of delivering flow up to 4.5 l/min at 7,500 rpm, however with a bilateral 12 Fr cannulation the flow is limited to 3.0 l/min. Heparin is usually administered continuously through the device lubrication system, and the activated clotting time should be maintained at 180-200 seconds. The current evidence of the TandemHeart™ is limited and there are no meaningful ongoing randomised clinical trials assessing the benefits of this device on clinical outcome [14, 122].

However, a single-centre study in patients with severe refractory cardiogenic shock despite IABP use and high-dose vasopressor support reported a “step-up” therapy with the TandemHeart™ [123]. Although being in severe refractory cardiogenic shock, the patients experienced significant haemodynamic improvements after LVAD implantation; the cardiac index improved from median 0.52 l/min/m2 to 3.0 l/min/m2; systolic blood pressure and mixed venous oxygen saturation increased from 75 mmHg to 100 mmHg and 49% to 69,3%, respectively; urine output increased from 70.7 ml/day to 1,200 ml/day; PCWP, serum lactate, and creatinine level decreased, respectively. The mortality rates at 30 days and 6 months were 40.2% and 45.3%, respectively which is remarkable given the severity of refractory cardiogenic shock [123].

Illustrative case 3 and moving images 7-22 show the individual steps of TandemHeart™ implantation.

Impella Family

The Impella^®(Abiomed Europe, Aachen, Germany) is placed across the aortic valve, using the femoral access, either percutaneously (Impela 2.5 and CP) or by surgical cut-down for the Impella 5.0 ( Figure 10 ; Illustrative case 4 and Moving image 23 [124, 125]. The Impella axial flow device incorporates an impeller—a rotor with helical blades that curves around a central shaft, driven by an electrical motor. The spinning of the impeller draws blood from the cannula positioned into the LV cavity, through the supporting the left ventricle device, to the outflow of the cannula in the ascending aorta. The device has a pigtail catheter at its tip to ensure a stable position in the LV and to prevent adherence to the myocardium.

As with all axial pumps, its performance depends on the rotary speed and the ‘pressure head’ (aortic pressure minus LV pressure, continuously monitored).

The experience with the Impella in CS patients remains limited [60]. Whether the ~1.8L/min of additional mechanical support provided by the smaller Impella Recover LP2.5 will be sufficient for patients with CS and/or circulator collapse is questionable [60]. The IMPRESS-IN-SEVERE-SHOCK trial compared the Impella CP versus IABP in 48 patients with cardiogenic shock complicating ST-elevation AMI [126]. This underpowered proof-of-concept trial failed to show any signal of mortality benefit with the Impella CP. However, it was also surprising that Impella CP support did not translate in benefits with respect to arterial lactate or other haemodynamic parameters.

In the setting of a lack of sufficient data from randomized controlled trials, matched comparisons provide the best second option evidence. A matched-pair mortality analysis of 237 Impella-treated versus 237 IABP-treated AMI-CS patients could confirm a lack of mortality benefit with the Impella device (30-day mortality 48.5% versus 46.4%, p=0.64[60]). Of note, severe or life-threatening bleeding (8.5% versus 3.0%, p<0.01) and peripheral vascular complications (9.8% versus 3.8%, p=0.01) were observed more frequently with the Impella device. A second propensity-matched analysis, involving 1680 pairs of AMI-CS patients, added further weight to this observation, actually suggesting potential harm with the use of Impella rather than IABP[127].Klicken oder tippen Sie hier, um Text einzugeben. Among the pairs, there was a significantly higher risk of in-hospital death associated with use of Impella versus IABP (absolute risk difference 10.9%, 95%CI 7.6–14.2%; p<0.001) and a higher risk of in-hospital major bleeding (absolute risk difference 15.4%, 95%CI 12.5–18.2%; p<0.001). These associations were consistent regardless of whether patients received a device before or after initiation of PCI.

A third recent publication assessed 4782 patients undergoing PCI treated with MCS in the US[128]. CS was present in 50%. After propensity adjustment, and accounting for clustering of patients by hospitals, Impella use compared to IABP was associated with an increased risk of death (OR 1.24, 95%CI 1.13–1.36), bleeding (OR 1.10, 95%CI 1.00-1.21) and stroke (OR 1.34, 95%CI 1.18-1.53). Interestingly, patients treated by Impella in comparison to IABP were less sick. Thus, a selection bias inherent to any observational data is less likely to be the cause of higher mortality with the Impella device.

Taken together, these results suggest that very careful patient selection for MCS is warranted, particularly in terms of weighing up the haemodynamic benefits against potential device-related complications. Due to the retrospective and non-randomised nature of these studies, it is possible, even allowing for complex statistical propensity matching, that unmeasured confounding is occurring.

Currently, there is another ongoing trial in Denmark and Germany (DanGer) assessing the effect of the Impella CP on 6-month mortality in CS patients (NCT01633502).

More promising in CS may be the Impella 5.0/LD. The Impella 5.0/LD is associated with favourable survival outcomes and higher rate of myocardial recovery in patients with cardiogenic shock in registry studies [46, 129].

Extracorporeal membrane oxygenation (Veno-arterial ECMO)

Patients may require ECMO because of cardiac failure, respiratory failure, or a combination thereof. VA-ECMO is a rapid option for emergency biventricular support. Integral features of ECLS are the blood pump, a heat exchanger, and an oxygenator. Blood is aspirated by a centrifugal pump from the right atrium through a long 17–21 Fr bypass cannula in the femoral vein and is returned by means of a heat exchanger membrane oxygenator to a femoral artery cannula (16-19 Fr); flow rates of up to 6 L/min may be obtained, providing nearly complete respiratory and circulatory support, independent of the intrinsic cardiac rhythm or ventricular function. Limb ischemia caused by femoral cannulation, can be prevented by distal leg perfusion with a small catheter (5-10 French) placed in the distal artery. The pump provides a continuous flow with maintenance of a pulsatile arterial pressure unless the circulation is completely supported by the system. Arterial and venous access can be obtained via peripheral cannulation of the femoral vessels, which can be applied rapidly at the bedside.

Centrifugal pumps operate in a fashion similar to that of some cardiopulmonary-bypass pumps. They typically consist of a cone-shaped rotor contained within a plastic or metal housing. Blood flows into the pump at the cone's apex and exits at the edge of the base. The spinning of the rotor creates a centrifugal force that is imparted to the blood, generating a constant, non-pulsatile flow.

There has been a gradual increase in rates of VA-ECMO use for CS over the past decade [130]. Regardless, outcome data on venous-arterial extracorporeal membrane oxygenation (VA-ECMO) in CS remain scarce. A recent metanalysis including only prospective and retrospective cohort studies revealed a significant mortality benefit with VA-ECMO use [131]. Survival of patients treated with VA-ECMO reflects the critical nature of the patients in whom it is used [132, 133]. In the specific setting of CS, the revival of extracorporeal circuitry and hardware that can provide both extended respiratory and or circulatory support to patients for periods up to several weeks may be of particular interest. Currently 3 large multicenter randomized outcomes trials with VA-ECMO in CS are ongoing (NCT04184635, NCT03813134, NCT03637205)

The concept of mechanical circulatory support with VA-ECMO relies on varying degrees of retrograde aortic flow to perfuse end organs [134]. A common issue related to peripheral cannula insertion in VA-ECMO is an increase in afterload which may lead to inadequate LV unloading. Multiple venting manoeuvres have been described to prevent volume overload such as combining VA-ECMO with IABP, Impella, atrial septostomy, or other. A recently published multicentre cohort study assessed if venting in patients with VA-ECMO was associated with lower mortality [135].Patients (n=225) with severe CS treated with VA-ECMO and Impella unloading (ECMELLA) were propensity matched with 225 patients treated with VA-ECMO without Impella. Left ventricular unloading was associated with lower 30-day mortality (HR 0.79, 95%CI 0.63-0.98; p=0.03) without differences in various subgroups. However, complications were noted to occur more frequently in the venting cohort, specifically severe bleeding (HR 2.87, 95%CI 1.92-4.35; p<0.01) and access site related ischaemia (HR 1.96, 95%CI 1.22-3.20; p<0.01). This study is in agreement with previous meta-analyses which have also shown a mortality benefit with unloading VA-ECMO [136]. Russo et al. identified 17 observational studies which included 3,997 patients receiving a concomitant LV unloading strategy while on VA-ECMO (IABP 91.7%, percutaneous ventricular assist device 5.5%, pulmonary vein or transseptal left atrial cannulation 2.8%). Mortality was 60% in the total cohort. The risk ratio for mortality was lower in those with venting than those without (RR 0.79, 95%CI 0.72-0.87; p<0.00001). There was no interaction between the specific unloading modalities and mortality. Kowalewski et al. conducted a similar metaanalysis, including 7581 patients from 62 observational studies [137]. An unloading strategy was associated with a lower mortality risk (RR 0.88, 95%CI 0.82-0.93; p<0.0001) and higher probability of VA-ECMO weaning (RR 1.35, 95% CI 1.21-1.51; p<0.00001).

A general treatment algorithm based on ESC guidelines with the respective guideline recommendations is shown in Figure 12 A-C and for the possible selection of mechanical circulatory support in Figure 13.

TREATMENT OF MECHANICAL COMPLICATIONS

Ventricular septal defect

Ventricular septal defect (VSD) complicating AMI is an infrequent event associated with high mortality. The incidence of infarct related VSD in the pre-thrombolytic era ranged from 1-2% [138, 139], with a decrease to 0.2% in the era of reperfusion [140]. The median time from infarction to rupture is usually 24 hours but may occur up to 2 weeks. Without surgical repair of post-infarction VSD, 90% of patients die within 2 months[141].

In 1957 Cooley and co-workers first described successful surgical correction of this lesion [142]. The current mortality of surgical post-infarction VSD closure is as high as 50%, which is not unexpected given the advanced patient age, comorbidities, severity of coronary artery disease, haemodynamic instability as well as technical challenges of the surgical procedure [143, 144]. In two prospective registries the mortality rates were as high as 81%-100% for patients with cardiogenic shock after development of an infarct related VSD which probably best reflects the current mortality for patients in cardiogenic shock caused by VSD occurrence [140, 145].

Current guidelines recommend immediate surgical VSD closure irrespective of the patient’s haemodynamic status to avoid further haemodynamic deterioration[21]. The septum is exposed to shear stress and necrotic tissue removal processes early after VSD occurrence, which may result in subsequent abrupt VSD expansion and sudden haemodynamic collapse. Nevertheless, a subgroup of patients with VSD exists for whom surgery is futile because mortality approaches 100%; this includes the very elderly and patients with poor RV function. It is well known that RV function is a more important determinant of outcome in VSD than the LV function [146].

As a result of the high mortality and suboptimal surgical results with a post-operative residual shunt found in up to 20% of treated patients, the technique of percutaneous VSD device closure has been developed[147]. Such less invasive approach with a catheter-based intervention may offer improved survival or provide haemodynamic stabilization as a bridge to surgery. Furthermore, it might be used as an adjunctive therapy for residual post-surgical shunts. The technique of post-infarction VSD closure, and potential technical improvements, has been described previously [148, 149, 150, 151]. In brief, after femoral artery puncture a 6-8 Fr sheath is inserted. The VSD is then crossed from the LV using a diagnostic or guiding right Judkins or a multipurpose catheter and a soft long guidewire, which is advanced into the pulmonary artery or the superior caval vein. The guidewire is then snared using a Gooseneck snare and exteriorised out of the right internal jugular vein, thereby establishing an arterial-venous circuit ( Figure 16 ); Illustrative Case 6 and Moving images 26-30). The delivery sheath of the umbrella occluder is then advanced via the jugular vein into the LV where the tip of the sheath is placed. After removal of the delivery sheath dilator and wire, the loaded flexible double-umbrella device can be advanced via the delivery sheath across the septal rupture into the LV. The umbrella device is pushed partially out of its catheter sheath until release of the first umbrella. The delivery catheter is afterwards drawn back into the RV until the left-sided umbrella is positioned against the LV septum. Finally the right-sided umbrella is released covering the rupture from the right side. During VSD occlusion, echocardiographic control is usually performed for device guidance, VSD visualisation, and VSD assessment. Some investigators prefer to use sizing balloons. However, this is difficult due to the complex anatomy of the ruptured septum and might even induce further damage to the septum.

Currently, data are limited for post-infarction VSD interventional closure[152]. Still, the largest single-centre experience in 29 patients reported a survival rate at 30 days of 35%, with much higher mortality in CS, as opposed to non-shock patients (88% vs 38%, p<0.001).[147] Procedure-related complications are frequent which further demonstrates the requirement of technical improvement. Procedure related complications such as major residual shunting, left ventricular rupture and device embolisation occurred in 41% in this series of patients which further demonstrates the requirement of technical improvement. A detailed flow diagram of the interventions performed, complications and potential additional surgery is shown in Figure 17 . The major limitations of current available umbrella devices used for VSD closure are shown in Focus box 6. Limitations of current available umbrella devices used for VSD closure.

Free wall rupture

Since many patients with free wall rupture present with sudden profound shock, often rapidly leading to pulseless electrical activity caused by pericardial tamponade, there are few treatment options. However, there might also be subacute presentations in case of a partial ‘’covered’’ rupture. Immediate pericardiocentesis can confirm the diagnosis in addition to echocardiography which is the cornerstone of diagnostic work-up. Pericardiocentesis relieves the cardiac tamponade at least momentarily for immediate surgical repair, if available. In a less acute clinical course this allows for potentially life-saving therapeutic interventions and in the most favourable situation also cardiac catheterisation to delineate the coronary anatomy if not already performed at initial presentation. However, this will also need surgical resection of the necrotic and ruptured myocardium with primary reconstruction and additional CABG, if required. In the SHOCK trial registry, 28 patients presented with pericardial rupture or tamponade [41]. The overall in-hospital mortality for this specific cohort was 39% which was not different from the overall cardiogenic shock cohort. In total 75% of the patients underwent surgery. However, this was a selected group of patients with not all having overt clinical free wall rupture which might explain the high surgical correction rate and also the relatively good outcome.

Acute ischaemic mitral regurgitation

In acute ischaemic mitral regurgitation only papillary muscle rupture needs immediate repair. Other causes such as LV global or regional remodelling or ischaemic papillary muscle dysfunction may resolve after revascularisation and recovery of LV function. Accordingly, only 46% of the patients in the SHOCK trial registry underwent mitral valve surgery [153].

In contrast to VSD repair, surgery of papillary muscle rupture does not involve necrotic myocardium in suture lines. Therefore, mortality associated with this repair is lower [153]. The unpredictability of rapid deterioration and death with papillary muscle rupture makes early surgery necessary even though there may be an initial apparent haemodynamic stabilisation with initial IABP therapy which is highly recommended by guidelines as a bridge to surgery, although no randomised data are available for this condition[21]. See Illustrative Case 7 and Moving images 31-36 in a patient with acute ischaemic mitral regurgitation.

Recently also, the first percutaneous approaches with the MitraClip system have been reported for the treatment of acute ischaemic mitral regurgitation with cardiogenic shock. However, current evidence is limited to only small case series [154, 155, 156].

TREATMENT OF RIGHT VENTRICULAR FAILURE

A major consideration for the overall cardiac output (CO) achieved in left-sided devices is residual RV function/dysfunction, which may only be assessed accurately on institution of left-sided support. RV failure is an ominous prognostic sign in CS. A detailed review of the pathophysiology and the treatment of cardiogenic shock from RV failure has been published previously [44, 157, 158]. As outlined in the pathophysiology section, it is of paramount importance to establish early reperfusion to reverse RV ischaemia, to maintain adequate RV preload with volume loading, to preserve RV synchrony (possibly using dual-chamber temporary pacing or even biventricular pacing) and to reduce the RV afterload by MCS and potentially inotropes. Effective reperfusion usually leads to rapid haemodynamic improvement.

The general principles of RV dysfunction management have been reviewed elsewhere [159]. These include (1) optimal volume management with or without vasopressor therapy; (2) optimization of heart rate; (3) enhanced RV inotropy and improved CI, usually with dobutamine; (4) reduction of RV afterload and pulmonary resistance. Lastly, the use of MCS with dedicated RV support or VA-ECMO may be considered in certain patients with refractory CS

The general management goals for patients in cardiogenic shock with right ventricular involvement are shown in Focus box 7. Management goals in right ventricular involvement.

FOCUS BOX 7Management goals in right ventricular involvement

Early recognition (right ventricular ECG, leads V3R, V4R, V5R, V6R)
Early reperfusion by PCI
Maintenance of right ventricular preload (volume management with central venous pressure aim: 15-18 mmHg)
Reduction of right ventricular afterload (inotropes, NO ventilation)
Preservation of right ventricular synchrony (Dual chamber pacing in case of AV block)
Avoidance of venous vasodilators (e.g., nitrates, morphine)
Mechanical circulatory support

MCS options for the temporary management of RV failure (including RV infarction) are currently being developed and studied. The Impella RP system (Abiomed, Figure 10) utilizes a catheter-mounted micro axial flow pump (see above) with the inflow just below the right atrium-inferior vena cava junction and the outflow into the pulmonary artery after insertion via the femoral vein. It is shaped differently than the left heart Impella devices to accommodate the right ventricular anatomy. Its impeller flow is also reversed from Impella LV devices to pump blood from the right atrium into the pulmonary artery toward the lungs. It includes a 22 French outflow. Due to the design of the system, internal jugular placement and ambulation are not possible.

Another option involves placing two cannulas – typically either two femoral venous cannulas or one femoral and one internal jugular venous cannula – with one cannula positioned in the right atrium and another in the pulmonary artery. This strategy employs an extracorporeal centrifugal pump with the inflow from the right atrial cannula and outflow to the pulmonary artery. Several different centrifugal flow pumps have been used with this cannulation strategy. As an alternative, a novel dual-lumen co-axial cannula flexible enough to be positioned with its distal tip in the pulmonary artery from internal jugular insertion can be used with a centrifugal flow pump to achieve a percutaneous RVAD [160, 161]. Because of its internal jugular cannulation site, this configuration allows for ambulation during the period of support. Removal is typically via a purse-string suture at bedside.

Personal perspective - Holger Thiele

The mortality of patients in cardiogenic shock remains extremely high. The incidence of cardiogenic shock, however, is declining slightly due to more rapid and efficient reperfusion by primary PCI. In case cardiogenic shock has developed it is crucially important to have a multidisciplinary team and a specialised centre for cardiogenic shock management to improve the clinical outcome of these patients with a dismal prognosis.

Randomised clinical trials in cardiogenic shock are difficult to perform and are often more costly than trials in other clinical conditions due to the complexity of the trial. Many believe that conducting a randomised study in this critically ill population is still not possible, due to the difficulties of enrolling and randomising these critically ill patients. However, as infarctions are frequent and cardiogenic shock inherent with high mortality, any intervention which reduces mortality is likely to have major public health implications and should therefore be thoroughly tested. In the era of evidence-based medicine, such trials are of paramount importance to achieve a breakthrough in cardiogenic shock treatment. Figure 16 gives an overview of completed randomized trials in cardiogenic shock (in blue) and also currently ongoing trials (in red).

Conducting randomised trials in such a population will require attention to methodology and the appropriate selection of the outcome parameters studied [32]. We have to realise that an improved haemodynamic status might not be a suitable surrogate marker for survival.

SHOWING 6 COMMENTS

Mahmoud Elrayes
30 December 2021, 13:18
Also, there is a duplicate of this paragraph Therefore, the current European Society of Cardiology (ESC) guidelines for revascularisation recommend immediate transfer of all STEMI and NSTE acute coronary syndrome patients for invasive evaluation and target vessel revascularisation (Class 1, Level of Evidence A recommendation) [69]. Immediate reperfusion is also indicated in acute heart failure with ongoing ischaemia (Class 1, Level of Evidence B recommendation) [69]. Therefore, the current European Society of Cardiology (ESC) guidelines for revascularisation recommend immediate transfer of all STEMI and NSTE acute coronary syndrome patients for invasive evaluation and target vessel revascularisation (Class 1, Level of Evidence A recommendation) [56]. Immediate reperfusion is also indicated in acute heart failure with ongoing ischaemia (Class 1, Level of Evidence B recommendation) [56].

Reply | You recommend it Recommend | You report it Report
Mahmoud Elrayes
30 December 2021, 12:58
Also in Table 3 ,you wrote beta receptor instead of alpha receptor.

Reply | You recommend it Recommend | You report it Report
Mahmoud Elrayes
30 December 2021, 11:05
This chapter needs rewriting and updates.There are 4 paragraphs under the title of pathophysiology that are duplicates of the paragraphs before and have no relation to pathophysiology. Also Focus Box 3 is of another chapter other than cardiogenic shock, may be high bleeding risk chapter. Thanks

Reply | You recommend it Recommend | You report it Report
Mohamed Gayed
4 January 2021, 10:44
Please, this chapter must be updated

Reply | You recommend it Recommend | You report it Report

Sonia Morcuende
7 January 2021, 17:29
Thank you for your comment. This chapter is due to benefit from an update in 2021. The editorial team

Reply | You recommend it Recommend | You report it Report

Abel Casso
17 February 2020, 17:58
This chapter needs to be updated. So much new and exciting data coming out for the management of cardiogenic shock in AMI.

Reply | You recommend it Recommend | You report it Report

Cardiogenic shock