**5. Treatment**

Since the most common etiology behind CS is ACS, the mainstay of therapy is coronary revascularization to relieve the vicious cycle of ischemia-shock state. Treatment also involves general supportive measures, pharmacotherapy, vasopressors, inotropes and mechanical circulatory support (MCS) in the setting of refractory shock (**Figure 4**).

#### **5.1. General measures and pharmacotherapy used in acute coronary syndrome**

All patients with suspected AMI—STEMI or NSTEMI—should receive a loading dose of aspirin (162–325 mg) as a chew non-enteric coated capsule and a maintenance dose of aspirin should be continued indefinitely after that. A high dose statin (atorvastatin 80 mg) is also indicated in all patients presenting with AMI without contraindications and should be continued indefinitely. Treatment with high dose statins for ACS patients reduced the risk of death, recurrent myocardial infarction, stroke and the need for coronary revascularization. Oxygen therapy is indicated for all patients with hypoxemia (O<sup>2</sup> saturation < 90%) [16, 21].

**Figure 4.** Cardiogenic shock treatment flow chart. CXR , chest X-ray; PA, pulmonary artery; EMBx, endomyocardial biopsy; A.C.S, acute coronary syndrome; BB, beta blockers; ACE-I, angiotensin converting enzyme inhibitors; ARB, angiotensin receptor blockers; LVAD, left ventricular assist device; Bi-VAD, biventricular assist device; CHF, congestive heart failure; GCM, giant cell myocarditis; TPA , tissue plasminogen activator; PE, pulmonary embolism; PH, pulmonary hypertension; PAH, pulmonary artery hypertension; BAV, balloon aortic valvuloplasty.

Beta blockers (BB), angiotensin converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARB) should be avoided in patients at risk for CS [16, 21].

In patients with STEMI, a loading dose of a P2Y12 inhibitor should be administered as early as possible or at the time of primary coronary intervention (PCI) (clopidogrel 600 mg, ticagrelor 180 mg or prasugrel 60 mg). Patients with NSTEMI who are undergoing early revascularization should also receive a loading dose of a P2Y12 inhibitor as soon as possible. It should be noted that prasugrel is contraindicated in patients with prior history of stroke or transient ischemic attack (TIA) [16, 21–23].

All patients with STEMI undergoing PCI should receive anticoagulation unless they have contra-indications. Unfractionated heparin (UFH) can be used with or without glycoprotein (GP) IIb/IIIA inhibitors. The recommended dose of UFH is 50–70 units/kg as IV bolus if used with GP IIb/IIIa inhibitors to achieve a therapeutic activated clotting time (ACT) of 200–250 s, or 70–100 u/kg as a bolus if used without GP IIb/IIIa inhibitors to achieve therapeutic ACT of (250–300 s). Bivalirudin can be used in STEMI patients as well, and is preferred as a monotherapy over the combination of UFH-GP IIb/IIIa inhibitor in patients at high risk for bleeding [21].

In patients with NSTEMI the anticoagulation regimen differs slightly from patients with STEMI, UFH can be used with a loading dose of 60 u/kg (maximum dose of 4000 units) followed by infusion of 12 u/kg/h with (maximum dose of 1000 u/h) adjusted to keep therapeutic activated partial thromboplastin time (PTT) during the period of treatment. Enoxaparin is another option for anticoagulation at a dose of 1 mg/kg every 12 h. Most NSTEMI patients presenting with CS will undergo early revascularization, which makes bivalirudin another good option for anticoagulation as bivalirudin is only indicated in NSTEMI patients who undergo early invasive strategy [16].

Most clinicians prefer to use UFH in the setting of CS complicating an NSTEMI given that most of these patients will undergo early invasive strategy, and UFH has the advantage to turn on and off, or even reverse rather easily.

GP IIb/IIIa inhibitors might be considered for NSTEMI patients undergoing early invasive strategy and are treated with dual antiplatelet therapy (DAPT) [16].

#### **5.2. Revascularization**

clinical picture is not clear, or when hemodynamic stabilization is not achieved despite escalating doses of vasopressors and inotropes. PA catheter is also recommended when mechanical circulatory support devices are considered. It should be noted that the routine use of PA catheter is discouraged in patients with a confirmed diagnosis and those who stabilize rather

Since the most common etiology behind CS is ACS, the mainstay of therapy is coronary revascularization to relieve the vicious cycle of ischemia-shock state. Treatment also involves general supportive measures, pharmacotherapy, vasopressors, inotropes and mechanical

All patients with suspected AMI—STEMI or NSTEMI—should receive a loading dose of aspirin (162–325 mg) as a chew non-enteric coated capsule and a maintenance dose of aspirin should be continued indefinitely after that. A high dose statin (atorvastatin 80 mg) is also indicated in all patients presenting with AMI without contraindications and should be continued indefinitely. Treatment with high dose statins for ACS patients reduced the risk of death, recurrent myocardial infarction, stroke and the need for coronary revascularization. Oxygen

**Figure 4.** Cardiogenic shock treatment flow chart. CXR , chest X-ray; PA, pulmonary artery; EMBx, endomyocardial biopsy; A.C.S, acute coronary syndrome; BB, beta blockers; ACE-I, angiotensin converting enzyme inhibitors; ARB, angiotensin receptor blockers; LVAD, left ventricular assist device; Bi-VAD, biventricular assist device; CHF, congestive heart failure; GCM, giant cell myocarditis; TPA , tissue plasminogen activator; PE, pulmonary embolism; PH, pulmonary

hypertension; PAH, pulmonary artery hypertension; BAV, balloon aortic valvuloplasty.

saturation < 90%) [16, 21].

circulatory support (MCS) in the setting of refractory shock (**Figure 4**).

therapy is indicated for all patients with hypoxemia (O<sup>2</sup>

**5.1. General measures and pharmacotherapy used in acute coronary syndrome**

quickly [20].

146 Interventional Cardiology

**5. Treatment**

Early revascularization is the cornerstone of treatment in AMI patients presenting with CS. The randomized SHOCK trial proved a statistically significant mortality benefit at 6 months in AMI patients complicated by CS treated with emergency revascularization as opposed to medical stabilization [5]. The non-randomized SHOCK registry also showed the same mortality benefit of early revascularization in patients older than 75 [24].

The goal in STEMI patients is first medical contact (FMC) to device time of less than 90 min, and revascularization can still be done even up to 12 h after ischemic symptoms onset. But, in patients with CS complicating a STEMI, revascularization should be performed regardless of the time of symptoms onset. It is also reasonable to intervene on non-infarct arteries in STEMI patients complicated by CS at the time of PCI [21].

Early revascularization within 2 h of presentation should be done in all NSTEMI patients with CS, as well as those with high-risk features (such as refractory angina, electrical instability, signs of heart failure or worsening mitral regurgitation, as well as sustained ventricular tachycardia or fibrillation) [16].

PCI is not the only option for revascularization; coronary artery bypass grafting (CABG) should be considered especially if successful PCI is not feasible, there are mechanical complications such as ventricular septal or papillary muscle rupture, and in those with left main disease or three vessels, CAD. Emergent CABG can be done within 2–4 h in capable facilities [16, 25].

Thirty-six percent of patients undergoing revascularization in the SHOCK trial underwent CABG; those patients were more likely to be diabetic and have left main or three vessels CAD. The survival rate at 30 days and at 1 year was similar between those who underwent PCI or CABG in the SHOCK trial [26].

Compared to patients without CS undergoing CABG, those with CS were more likely to have had suffered AMI within 24 h prior to CABG, were more likely to have left main disease, have lower ejection fraction and were more likely to have intra-aortic balloon pump (IABP) used preoperatively [25].

It should be noted that patients with CS undergoing CABG have worse morbidity and mortality and longer intensive care unit (ICU) stay than those without CS. And even though older age was associated with higher morbidity and mortality, around 70% of patients with CS above the age of 75 survived this major surgery making CABG suitable for carefully selected elderly CS patients [25].

### **5.3. Fibrinolysis**

If PCI cannot be performed within 120 min of FMC in STEMI patients, fibrinolytics can be used in those without contraindications and even up to 12 h after symptoms onset, and up to 24 h in those with large areas of ischemia, hemodynamic instability, or have clinical or ECG signs of continuous ischemia. **Table 2** summarizes the absolute contraindications to fibrinolysis [21].


**Table 2.** Absolute contraindications to fibrinolytics [21].

Patients with RV infarction secondary to proximal right coronary artery (RCA) occlusion with extensive clot burden might be resistant to fibrinolytic therapy; there is also a higher rate of re-occlusion after thrombolysis of the RCA [13, 27, 28].

Patients with CS secondary to STEMI who are treated with fibrinolytics should be transferred immediately to a PCI-capable facility after receiving fibrinolysis.

In patients with NSTEMI, fibrinolytics are contraindicated; those patients should be stabilized and transferred immediately to a PCI-capable facility for coronary angiography and revascularization [16].

#### **5.4. Vasopressors and inotropes**

Early revascularization within 2 h of presentation should be done in all NSTEMI patients with CS, as well as those with high-risk features (such as refractory angina, electrical instability, signs of heart failure or worsening mitral regurgitation, as well as sustained ventricular

PCI is not the only option for revascularization; coronary artery bypass grafting (CABG) should be considered especially if successful PCI is not feasible, there are mechanical complications such as ventricular septal or papillary muscle rupture, and in those with left main disease or three vessels, CAD. Emergent CABG can be done within 2–4 h in capable facilities

Thirty-six percent of patients undergoing revascularization in the SHOCK trial underwent CABG; those patients were more likely to be diabetic and have left main or three vessels CAD. The survival rate at 30 days and at 1 year was similar between those who underwent PCI or

Compared to patients without CS undergoing CABG, those with CS were more likely to have had suffered AMI within 24 h prior to CABG, were more likely to have left main disease, have lower ejection fraction and were more likely to have intra-aortic balloon pump (IABP) used

It should be noted that patients with CS undergoing CABG have worse morbidity and mortality and longer intensive care unit (ICU) stay than those without CS. And even though older age was associated with higher morbidity and mortality, around 70% of patients with CS above the age of 75 survived this major surgery making CABG suitable for carefully selected

If PCI cannot be performed within 120 min of FMC in STEMI patients, fibrinolytics can be used in those without contraindications and even up to 12 h after symptoms onset, and up to 24 h in those with large areas of ischemia, hemodynamic instability, or have clinical or ECG signs of continuous ischemia. **Table 2** summarizes the absolute contraindications to

Any prior intracranial hemorrhage Any active bleeding or bleeding diathesis (not including

Known cerebral structural vascular lesion Ischemic stroke within the past 3 months (except for

Severe uncontrolled refractory hypertension Any significant closed head or facial trauma in the past

Intracranial or intraspinal surgery in the past 2 months If streptokinase is used, prior treatment within the

Known malignant intracranial neoplasm Suspected aortic dissection

**Table 2.** Absolute contraindications to fibrinolytics [21].

menses)

3 months

those with ischemic stroke in the past 4.5 h)

previous 6 months (streptokinase is antigenic)

tachycardia or fibrillation) [16].

CABG in the SHOCK trial [26].

preoperatively [25].

elderly CS patients [25].

**5.3. Fibrinolysis**

fibrinolysis [21].

[16, 25].

148 Interventional Cardiology

There is no optimal vasopressor or inotrope in the setting of CS, but catecholamines are the most frequently used vasopressors, with norepinephrine and dopamine being the most widely used. Catecholamines exhibit their effects through the stimulation of A1, B1, B2, and dopaminergic receptors (D1 and D2) [9, 29].

Norepinephrine is a potent A1 agonist; it induces an increase in systolic blood pressure (SBP), diastolic blood pressure (DBP), and the pulse pressure. Norepinephrine has minimal effect on myocardial contractility and HR [29].

Dopamine produces a multitude of effects at different doses: at lower doses (<3 ug/kg/min), it works primarily on the D1 receptors and causes coronary and renal vasodilatation; at intermediate doses (3–10 ug/kg/min), dopamine stimulates the B receptors and causes an increase in inotropy and HR; and at higher doses (10–20 ug/kg/min), dopamine works primarily on A1 receptors and causes vasoconstriction. The renal vasodilatory effect—so-called renal dose of low dose dopamine remains controversial, and glomerular filtration rate (GFR) does not change with use of those renal doses of dopamine [30, 31].

Epinephrine has high affinity towards A1, B1 and B2 receptors, with B effects more pronounced at lower doses and Alpha effects at higher doses. Prolonged use of epinephrine is associated with direct cardiac toxicity through damage to the arterial wall that results in myocardial necrosis and stimulation of myocyte apoptosis [29, 32].

Vasopressin or "antidiuretic hormone" is a non-adrenergic vasopressor; it stimulates the V1 and V2 receptors. The stimulation of the V1 receptors causes vasoconstriction while the stimulation of the V2 receptors enhances water reabsorption in the renal collecting ducts. It augments the pressor effect of norepinephrine and has no effect on cardiac output (CO). Vasopressin's pressor effect is relatively preserved during the acidotic state that develops in most shock patients [29, 33].

Dobutamine is a B1 and B2 agonist; it primarily induces an inotropic effect, exhibits a modest increase in HR and causes peripheral vasodilatation through the stimulation of B2 receptors. Dobutamine induces an increase in the cardiac output and a reduction in the LVEDP. Pharmacologic tolerance to dobutamine usually develops after 72 h of use. Dobutamine could induce arrhythmias, myocardial ischemia and tachycardia, especially at higher doses (>15 ug/kg/ min), but these effects are reversed rather rapidly due to the short half-life of the drug (2.3 min). The prolonged use of dobutamine (7–52 days) is associated with much higher 6-month mortality [29, 30, 34–36].

Milrinone is a noncatecholamine inotrope and peripheral vasodilator, has lusitropic effect and has less effect on HR than dobutamine. Milrinone works through the inhibition of phosphodiesterase enzymes (PDE), which in turn, leads to an increase in intracellular cyclic adenosine monophosphate (cAMP), which leads to an increase in the rate of entry and removal of calcium from the cardiac myocytes thus increasing myocardial contractility. Milrinone has been mainly used in the treatment of advanced severe heart failure patients, and—to date there have been head-to-head trials comparing dobutamine to milrinone. Milrinone should be avoided in advanced kidney disease patients as it is cleared renally [30, 37, 38].

Levosimendan is a calcium-sensitizing agent that enhances myocardial inotropy and lusitropy and causes peripheral vasodilation, and it is not yet approved for use in the USA. Levosimendan is associated with similar mortality rates as compared to dobutamine but it tends to cause more peripheral vasodilation and hypotension than dobutamine [30, 39, 40].

Norepinephrine is preferred over dopamine as dopamine has been associated with a higher incidence of arrhythmias and a higher rate of death at 28 days in the CS patient subgroup [3].

In CS secondary to RV infarction, IV fluids are always the first line, but the excessive administration of IV fluids beyond an RA pressure of 15 mmHg could result in the deterioration of LV performance, and the use of dobutamine in this scenario can be particularly helpful in improving myocardial performance. Despite the severe hemodynamic compromise, arrhythmias, and increased in-hospital mortality, many patients with severe RV infarction recover within 3–10 days and typically, global RV function recovers within 3–12 months [13, 29, 41].

Vasopressors and inotropes are essential in stabilizing CS patients but caution should always be taken with their use. The use of these agents causes an increase in the myocardial oxygen demand and can induce arrhythmias, and thus their use should always be individualized and guided by hemodynamic monitoring. The long-term use of inotropes is strongly discouraged, and should only be considered as a bridge to heart transplantation or ventricular assist devices (VAD) or as a palliative therapy in advanced heart failure patients [20, 29].

It is recommended to combine two small doses of vasopressors and inotropes than the use of a maximal dose of a single agent to avoid dose-related adverse events, also, the addition of vasopressin can help with "catecholamine sparing" [29]. The use of epinephrine in CS patients is associated with higher 90-day mortality independent of a prior cardiac arrest, and, thus, its use is discouraged unless it is a last resort medication [42].

Our experience with these vasoactive agents in CS has been to initiate norepinephrine followed by an inotrope and then a stepwise approach in the addition of further vasopressors and/or inotropes in the setting of refractory shock. A concomitant shock etiology, such as septic shock, should always be investigated as the choice of these agents might differ.

References [20, 29] provide further information about inotropes and their mechanism of action.
