When cardiac output decreases sufficiently, both systemic and coronary perfusion are lowered. Coronary perfusion moreover drops through a double mechanism, since there is also an increase in intraventricular diastolic pressure. The decrease in myocardial perfusion in turn induces or worsens ischemia, generating a vicious circle of increased cardiac dysfunction and lowered cardiac output.

At the systemic level, the baroreceptors activate a sympathetic response with the release of catecholamines that elevate the heart rate, venous tone and arterial vasoconstriction, to increase peripheral and coronary perfusion. However, this in turn causes an increase in afterload, with the consequent rise in filling pressures and overload of the already damaged myocardium.16,19 In addition, due to the increase in arteriolar and venous vasoconstriction, a gradient is produced that results in fluid displacement from the non-stressed to the stressed compartment, generating increased congestion.

Renal hypoperfusion activates the renin-angiotensin-aldosterone axis.15 Angiotensin produces peripheral vasoconstriction, contributing to the increase in cardiac afterload. In turn, aldosterone causes water and sodium retention, seeking to increase the circulating volume – an effect that adds to the secretion of antidiuretic hormone, thereby worsening congestion.

When these mechanisms are exceeded and cardiac output is unable to meet the metabolic and oxygen demands of the tissues, the latter enter anaerobic metabolism, generating lactic acidosis and depletion of the adenosine triphosphate (ATP) reserves. This in turn leads to worsening of cardiac output, which moreover can be adversely affected by arrhythmias or mechanical complications.

Ischemia sets in and a proinflammatory state is generated in the form of a systemic inflammatory response syndrome. This state is characterized by the release of cytokines, tumor necrosis factor-alfa (TNF-α), free radicals and nitric oxide synthase (NOS), producing vasodilatation through microvascular resistance to catecholamines20 and increased depression of myocardial function secondary to a decrease in beta receptor expression. Another substance released in the context of hypoperfusion is interleukin-6 (IL-6), which is independently associated with early mortality in patients with acute myocardial infarction.21

The pro-inflammatory state produces endothelial dysfunction, resulting in capillary leakage that contributes to multiorgan dysfunction.22 Under normal conditions, the glycocalyx covers the luminal surface of the endothelium, preserving its integrity and avoiding platelet aggregation and coagulation. When the glycocalyx loses its integrity, endothelial activation occurs, with platelet and leukocyte adhesion and activation of the coagulation cascade, producing thrombosis and microvascular occlusion.23

These microcirculatory disorders may appear from the early stages of CS, when no macrocirculatory alterations have yet developed, and are associated with a poorer prognosis.24

The activation of leukocytes and monocytes results in the secretion of large amounts of myeloperoxidase, which in turn generates reactive oxygen species (ROS), damaging the myocardial cells and altering the vascular tone.20 On the other hand, the mitochondrial DNA of the damaged cells that is released and circulates in blood induces a potent inflammatory response mediated by Toll-like receptor 9 (TLR-9), which identifies it as a foreign material in a way similar to the response that occurs in septic shock when bacterial material is detected.25

As hypoperfusion becomes generalized and anaerobic metabolism sets in, several initially reversible organ dysfunctions develop. Hypoxia and metabolic acidosis of lactic acid origin produce a decrease in vascular resistance at the arteriolar level, worsening vasoplegia and amplifying the inflammatory response.12

Liver and renal dysfunction secondary to hypoperfusion and congestion is associated with metabolic, ionic and water alterations and coagulopathy. The neurological exploration may reveal drowsiness and coma or, contrarily, psychomotor agitation. At the pulmonary level, congestion favors the appearance of edema and therefore of hypoxia, which will affect both the already ischemic myocardium and the rest of the organs. Gastrointestinal hypoperfusion in turn facilitates bacterial translocation, favoring the appearance of sepsis, and bleeding.

The initial cardiac dysfunction, tissue hypoperfusion and multiorgan dysfunction generate increasingly greater hypotension that worsens the ischemia, perpetuating a vicious circle that becomes irreversible.16,26 Once this point of no return has been reached, and even if tissue perfusion is restored by the measures adopted to revert the condition, it is unlikely that the death of the patient can be avoided.

Several mortality risk factors in CS have been identified, with the severity of shock being one of the most potent predictors and the factor most widely used in the existing classifications.27,29 There is great heterogeneity in the definition of severity, however, and the lack of standardization constitutes a limitation both for communication between care teams and for the comparison of results in the research setting.

Of the individual severity parameters associated with the prognosis of CS, mention should be made of the following:

• 1

  Grade of hypoperfusion. Lactate concentrations > 4–5 mmol/l upon admission imply a poorer prognosis, particularly when the levels exceed 10 mmol/l. A lack of lactate clearance and more acid pH levels have also been associated with a poor prognosis.10,30–33

• 2

  Hemodynamic condition of the patient. Arterial hypotension, tachycardia, low cardiac output, loss of contractility (low stroke volume, cardiac work index), right ventricle dysfunction and systemic congestion.10,28,29,33,34

• 3

  Intensity of the circulatory support measures. A poorer prognosis is associated with a need for more vasoactive drugs, in terms of both the number of vasopressors and inotropic agents, and their dosage.35 Indices such as the Vasoactive Inotropic Score or the Norepinephrine Equivalent Dose have been associated with mortality, integrating the arterial pressure reached and the need for mechanical circulatory support (MCS) as a modifier of amine dosage.36–38

• 4

  Cardiac arrest (CA) recovery. Independently of its duration and the care level at which it occurs, and particularly when associated with anoxic brain damage, the prognosis is poor even when shock improves with treatment.13,39,40

• 5

  Secondary inflammatory response grade.41

To determine the prognosis of CS we also must take into account several non-modifiable factors inherent to the patient. In this regard, age is the factor with the strongest impact on the prognosis. Other characteristics, such as frailty, comorbidities or gender and race are less consistent between different studies in terms of impact.42–44

At present, the most popular classification for CS in clinical practice and in research is that of the Society for Cardiovascular Angiography and Interventions (SCAI).13 This scale stratifies the patients into 5 levels or stages of severity (A, B, C, D, E) using parameters referred to the clinical, hemodynamic and biochemical situation (perfusion and organ function), with cardiac arrest recovery acting as an unfavorable prognostic modifier represented under subtype A (Table 1).

Several studies have validated the scale in different centers and countries, applied to both CS-ACS and CS-NoACS. These publications show SCAI to be correlated to the patient prognosis, with greater short and long-term mortality corresponding to higher stages, even on stratifying the population according to the diagnosis, non-modifiable risk factors, intensity of treatment, shock phenotype and comorbidity. This capacity has been demonstrated when the scale is used upon admission, with the poorest values in the first 24 h, or even with the poorest values during patient stay. The short-term mortality rate is 3% in stage A and increases to 7% in stage B, with a four-fold increase in stage C (10%–35%), and reaches 25%–68% in stage D and 45%–85% in stage E.

The SCAI could have a favorable impact when used as a triage tool, offering a window of opportunity for early detection, treatment adjustment or even patient transfer to a reference center in order to avoid CS progression and improve the prognosis.39

Nevertheless, the SCAI still presents some points of controversy that need to be resolved, such as the definition of normotensive CS in stage B, the cut-off points of the hemodynamic and laboratory test variables used, the degree of neurological involvement for introducing subtype A in the case of cardiac arrest, or the use of the scale in other types of shock.45

A review of the SCAI shows that even within each stage there are different levels of severity with different prognoses, conditioned to certain characteristics of the patient and the clinical situation. These factors act as risk modifiers; consequently, the use of a triaxial assessment model is proposed, taking into account patient severity according to the SCAI stage, the shock phenotype and the risk modifiers39,45 (Fig. 3).

Figure 3.

Triaxial assessment of patients with cardiogenic shock (CS).

*Echocardiographic alterations: Left ventricular ejection fraction (LVEF) < 40% and early mitral valve insufficiency.

**Hemodynamic alterations: Cardiac index (CI) < 1.8 ml/kg/m2, Systolic volume index (SVI) < 35 ml/m2, Cardiac power output (CPO) < 0.6 W.

LV: Left ventricle; RV: Right ventricle.

(0.39MB).

The shock phenotype refers to the concrete hemodynamic profile of the patient. It is defined using clinical, biochemical, echocardiographic and invasive monitoring criteria, with the distinction of three differential prognostic profiles44,46:

• 1

  Non-congestive, characterized by isolated left side dysfunction without congestion and with little organ damage.

• 2

  Cardiorenal, characterized by significant left-side dysfunction, renal damage and pulmonary congestion.

• 3

  Cardiometabolic or hemometabolic, characterized by right ventricle dysfunction, systemic congestion, lactic acidosis and multiorgan dysfunction.

Using the phenotype and SCAI, the mortality rate progresses from 6% in non-congestive stage C to 29% in cardiometabolic stage C – exceeding mortality in non-congestive stage D (17%). A greater inflammatory component with the corresponding loss of peripheral vascular tone is likewise related to a poorer prognosis. Use has been made of the neutrophil/lymphocyte ratio (NLR) to estimate inflammatory activity, and in this regard, considering a value of <3.5 in the controls, the ratio is associated with a 1.05-fold increase in mortality for every 3.5 points of increase in NLR. Stage B with inflammation presents greater mortality than stage C without inflammation.46

The detection of CS should begin at first medical contact with the patient (including out-of-hospital contact), and should be based on the evaluation of clinical signs (SBP < 90 mmHg or MBP < 60 mmHg, lethargy, coldness, diuresis < 30 ml/h) and laboratory test data (serum lactate > 2 mmol/l, BNP or NT-proBNP > 100 or 300 pg/ml, elevated urea and/or creatinine) indicative of hypoperfusion.47

It must be taken into account that the clinical signs are not specific to CS. In this regard, patients with advanced heart failure may present clinical and hemodynamic profiles that emulate CS without the latter actually being present. Likewise, hypertensive patients or individuals in the early stages of CS when pressure compensation of hypoperfusion is still active might not show hypotension, and in high-risk pre-shock patients the imminent development of shock might go unnoticed.

With regard to the laboratory test data, it should be noted that while lactate is a good indicator of the degree of hypoperfusion, has a high prognostic value, and is correlated to the degree of organ recovery and survival, it also may be elevated in other situations (diabetic ketoacidosis, trauma, liver failure, use of adrenaline, linezolid, propofol) that must be considered in the differential diagnosis.57 In the case of BNP, we also must take into account that elevations can be observed in a broad range of cardiac and non-cardiac conditions; the determination of BNP therefore should be made in cases where no firm diagnosis is available.47 On the other hand, troponin can be useful for the diagnosis of ACS. Table 3 describes the different diagnostic tests to be performed on patients with CS.

During the entire initial CS evaluation phase, it is essential to start an etiological study that subsequently will be completed in the next phase, seeking the presence of a potentially reversible triggering or coexisting cause that should be treated immediately (acute myocardial infarction code),43,55 or which implies the activation of other time-dependent disease conditions (sepsis code).

Once the signs of hypoperfusion have been established, careful patient evaluation is necessary, using continuous monitoring of cardiac rhythm, respiratory rate, oxygen saturation and blood pressure, and the etiological study should be completed.14,58,59 In this regard, a 12-lead electrocardiogram should be obtained to evidence myocardial ischemia or alterations in cardiac rhythm capable of accounting for the patient's condition, and an echocardiographic study should be made to identify possible underlying causes and explain the associated pathophysiological process.43,47 These tests are essential and are systematically recommended in the evaluation of shock patients, particularly when considering that if the underlying cause is not identified and treated, the outcome usually proves fatal despite adequate hemodynamic management of CS.60,61

Initial echocardiographic evaluation, which may be performed on a point-of-care basis,62 is required to clarify the type of shock, with a due evaluation of the function of both ventricles, determination of the presence of diseases conditioning shock (Table 3), and conduction of a first hemodynamic evaluation to assess the presence of elevated ventricular filling pressures.14,61 Then, and especially in cases of progressive worsening or high SCAI levels, an echocardiographic evaluation should be made (transthoracic or transesophageal) by an expert with advanced knowledge of ultrasound to confirm the etiology, assess the hemodynamic situation, guide volume response based on static and dynamic parameters,61,63,64 and orientate pharmacological treatment and the use of MCS devices (ECMO) and/or ventricular assist measures (counterpulsation balloon, Impella®).65,66 In addition to echocardiographic assessment, pulmonary ultrasound67 and chest X-rays are very useful, since they allow us to evaluate the degree of pulmonary congestion, discard other disease conditions that could explain the clinical condition, and confirm the positioning of catheters and cardiac devices.14

In cases of hemodynamic instability and/or progression of the disorder, it is advisable to use invasive arterial monitoring and place a central venous catheter for continuous measurements of pressures and biochemical parameters, and guidance at the start of initial treatment.14,43,68

The use of a pulmonary artery catheter for initial shock evaluation is controversial and is probably not advisable on a systematic basis – reserving it for selected patients that fail to respond to initial therapy, or situations in which greater precision is needed in evaluating the shock phenotype in order to guide patient management.12,43

As we have seen, the stratification of patients with CS based on the SCAI scale and identification of the different phenotypes allows rapid risk assessment, unifies communication between care levels, and thus improves the patient prognosis. Since progression over the continuum of SCAI levels is a dynamic process that incorporates new information as it becomes available, this phase should be started from first contact with the patient, overlapping in time with the hemodynamic evaluation and identification phases (Fig. 4).