Cardiogenic shock medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammad Salih, MD. João André Alves Silva, M.D. [2]; Rim Halaby, M.D. [3] Syed Musadiq Ali M.B.B.S.[4]

Overview

Cardiogenic shock is a medical emergency, rescusitive measures should be initiated immediately while the underlying etiology of the cardiogenic shock is promptly investigated. Myocardial infarction (MI) is the most common cause of cardiogenic shock, and when present, prompt revascularization should be performed. Other causes, such as free wall rupture, acute valvular abnormality, or left ventricular septum rupture, may require more invasive interventions. The management plan of cardiogenic shock includes the initiation of resuscitation and general measures, optimization of the blood pressure (pharmacological therapy or mechanical therapy when hypotension is refractory to inotrope and vasopressors), reperfusion or revascularization, and hemodynamic monitoring and stabilization. Urgent revascularization is a priority over hemodynamic monitoring in MI patients with cardiogenic shock and should not be delayed. The first line strategy for reperfusion is percutaneous coronary intervention which is preffered over coronary artery bypass graft (CABG), when PCI or CABG can not be perfomed, fibrinolytic therapy is indicated in the absence of any contraindications.

Medical Therapy

Goals of Therapy

Cardiogenic shock is characterized by low cardiac output, high left ventricular filling pressure, and decreased blood pressure with organ hypoperfusion. Goals of therapy:

• Increase coronary blood flow
• Decrease myocardial energy consumption
• Increase systemic blood flow

Management Plan

• Resuscitation and general measures
• Optimization of the blood pressure
  • Pharmacological therapy
  • Mechanical therapy
• Reperfusion or revascularization
• Hemodynamic monitoring and stabilization

Resuscitation and General Measures

Resuscitation measures should be IMMEDIATELY initiated:

• Monitor heart rate
• Monitor blood pressure (sphygmomanometer or arterial line)
• Correct hypoxia and ensure optimal oxygenation and ventilation support (mechanical ventilation is often required in patients with cardiogenic shock to assure adequate oxygenation.)
• Correct electrolytes and acid base abnormalities
• Manage the intravenous volume status
• Pain relief
• Anti-thrombotic therapy among patients with MI: aspirin, heparin, possibly GPIIbIIIa inhibitor
• Check the glucose and administer insulin in case of severe hyperglycemia
• Monitor ECG and restore sinus rhythm

Optimization of the Blood Pressure

The goal of blood pressure optimization are to:

• Improve coronary blood flow
• Improve systemic reperfusion

The first line treatment to increase blood pressure in cardiogenic shock is the administration of pharmacological therapy with either ionotropes or vasopressors. If pharmacological therapy fails to stabilize the patient's blood pressure, mechanical support must be provided.

Pharmacological Therapy

The appropriate choice of an inotrope or vasopressor requires the assessment of the balance between its desired and undesired effects:

• Desired effects: ↑ cardiac output and ↓ left ventricular pressure
• Undesired effects: ↑ myocardial energy consumption

All inotropes and vasopressors increase myocardial oxygen consumption to a certain extent. However, the benefit of their administration in the setting of a cardiogenic shock is achieved through counteracting the deleterious effects of hypotension. In cardiogenic shock, hypotension decreases myocardial perfusion and leads to compensatory elevation in LV filling pressure which in turn increases myocardial energy consumption. Therefore, the balance between desired and undesired effects of these agents necessitate their administration at the minimum efficacious dose. There is no robust data that compares the efficacy of inotropes and vasopressors in improvement of cardiovascular outcomes and reduction in mortality.

The two main agents used to optimize the blood pressure are Dopamine, dobutamine (mainly among non-sick patients), and norepinephrine (mainly among patients with severe hypotension). Alternative agents include phosphodiesterase inhibitors (amrinone or milrinone) and levosimendan. The choices of pharmacological agents is guided by the blood pressure and clinical status of the patient. There is no clear cut regarding the choice of the agents, combinations of moderate doses of different medications are commonly used instead of the administration of the maximal dose of any individual drug.

Low Output without Shock

Dobutamine is the treatment of choice among non-sick patients with low output and preserved systolic blood pressure.

Low Output with Shock

Systolic Blood Pressure (SBP) > 70 or 80 mm Hg

Dobutamine is preferred over dopamine when the patient does not have symptoms:

• Usual dose: 2.0–20 μg/kg/min
• Maximum dose: 40 μg/kg/min
• Avoid ↑ HR by >10% of baseline

Dopamine should be administered among symptomatic patients:

• Cardiac dose: 5.0–10 μg/kg/min
• Pressor dose: 10–20 μg/kg/min
• Maximum dose: 20–50 μg/kg/min

Phosphodiesterase inhibitors (PDIs) such as milrinone and inamrinone (formerly known as amrinone) are not dependent upon the adrenoreceptor activity and patients may not develop tolerance, and they may be less likely to increase myocardial oxygen demands and risks of arrhythmia. However, the addition of a vasopressor is often required as these agents reduce preload and afterload. PDIs are more likely to be associated with tachyarrhythmias than dobutamine, significant vasodilation and hypotension.

Systolic Blood Pressure (SBP) < 70 or 80 mm Hg

Norepinephrine is indicated among patients with severe hypotension:

• Initial dose: 0.5–1.0 μg/min
• Maximum dose: 30–40 μg/min
• Titrate to SBP >90 mm Hg

If norepinephrine does not generate a MAP of 60 mm Hg, then epinephrine can be added. Epinephrine increases both the stroke volume and heart rate, but is associated with an increased rate of lactic acidosis.

Mechanism of Action of Ionotropes and Vasopressors

Shown below is a table summarizing the different inotrope or vasopressor agents used in the setting of cardiogenic shock.

Drug	Alpha 1	Beta 1	Beta 2	Dopamine	Effects
Norepinephrine	+++	++	+	-	Minimal to moderate inotropic effect Minimal chronotropic effect Increase systolic and diastolic BP Minimal impact on CO Potent vasoconstriction Increase coronary blood flow (increase diastolic BP)
Dopamine (dose---)	++	++	-	++	Increase CO Increase BP and SVR Increase myocardial consumption Increase renal perfusion and urine output Peripheral vasoconstriction Increases PCWP
Dobutamine	+	+++	++	-	Increase CO Increase myocardial contractility Decrease LV filling pressure Increase coronary flow during diastole Increase collateral blood flow to ischemic regions Vasoconstriction Less arrythmogenic
Isoprotenerol	-	+++	+++	-	* Positive inotrope Positive chronotrope Decrease coronary reperfusion No effect of CO Arrhythmogenic Consider ONLY in patients with bradyarrhythmia as a bridge to temporary pacemaker
Phenylephrine	+++	-	-	-	Reflex bradycardia Vasoconstriction
Epinephrine	+++	+++	++	-	* Arrythmogenic Increase myocardial contractility

Phosphodiesterase inhibitors (milrinone, amrinone):

• Potent ionotrope
• Potent chronotrope
• Vasodilation
• Increase myocardial contractility

Vasopressin:

• Act on V1 (vascular smooth muscle cells) and V2 (renal collecting duct system) receptors
• May cause cardiac ischemia
• Severe peripheral and splanchnic vasoconstriction

Levosimendan:

• Used mainly in decompensated heart failure

Mechanical Therapy

Mechanical therapy for cardiac shock involves the use of circulatory assist systems, which are different by:

• Mode of placement: percutaneous vs. surgical
• Mode of circulatory support: LV, RV, or biventricular and/or volume unloading
• Presence or absence of combined extracorporal membrane oxygenation (ECMO)

Intra-Aortic Balloon Pump (IABP)

As per the recommendation of the 2013 AHA/ACC guidelines, in the setting of acute MI complicated by cardiogenic shock refractory to pharmacological therapy, the placement of an intra-aortic balloon pump (IABP) (which reduces workload for the heart, and improves perfusion of the coronary arteries) should be considered (Class IIa, level of evidence B).

The hemodynamic effects of IABP are:

• ↑ stroke volume and cardiac output
• ↑ systemic blood pressure
• ↑ coronary blood flow
• ↓ myocardial oxygen consumption
• ↓ pulmonary capillary wedge pressure

Despite IABP's favorable hemodymaic benefits, the survival benefit associated with the use of IABP is controversial. An analysis from the National Registry of Myocardial Infarction (NRMI) database indicates that in-hospital mortality rates are decreased at hospitals with higher rates of IABP insertion for cardiogenic shock complicating STEMI. The raw mortality was 65.4% at hopsitals in the lowest volume tertile (3.4 IABPs/year); 54.1% at hopsitals with intermediate volume (12.7 IABPs/year); and 50.6% for hospitals with the highest volume (37.4 IABPs/yr)(P for trend <0.001). This difference in mortality would yield 150 fewer deaths per 1000 patients treated at the high IABP hospitals. Even in a multivariate analysis, hospitals with the highest IABP volume had the lowest mortality (OR=0.71, 95% CI=0.56 to 0.90), independent of baseline patient characteristics, hospital factors, treatment, and procedures such as PTCA. In the Euro Heart Survey on PCI among 654 MI patients with cardiogenic shock, the use of IABP was associated with non-statistically significant reduction in mortality.

Clinical outcome studies also demonstrate conflicting results regarding the use of IABP and improved survival. In a Cochrane database systematic review among 190 patients, the use of IABP was not associated with a reduction in all-cause 30-day mortality (HR=1.04; 95% confidence interval 0.62–1.73). In another meta-analysis of 9 cohorts (n = 10529), the use of IABP was associated with 18% decrease (p<0.0001) and and 6% increase (p<0.0008) in 30-day mortality among STEMI patients with cardiogenic shock treated with fibrinolytic therapy and those undergoing primary PCI, respectively. In a meta-analysis of seven randomized trials among 1009 patient, IABP placement in STEMI was not associated with an improvement in mortality or in left ventricular function but was associated with a higher rate of stroke and bleeding. When data from non-randomized cohort studies were evaluated in a meta-analysis (n=10,529 STEMI patients with cardiogenic shock), IABP placement was associated with an 18% relative risk reduction in 30 day mortality among patients treated with a fibrinolytic agent. This particular analysis is confounded by the fact that those patients in whom an IABP was placed underwent adjunctive percutaneous intervention (PCI) more frequently. In this non-randomized cohort analysis, IABP placement in patients undergoing primary angioplasty was associated with a 6% relative increase in mortality (p<0.0008). Thus, neither randomized nor observational data support IABP placement in the setting of primary PCI for cardiogenic shock, and careful consideration should be given to the risk of stroke and bleeding prior to IABP placement in this population.

Left Ventricular Assist Device (LVAD)

As per the recommendation of the 2013 AHA/ACC guidelines, in the setting of pronounced hypotension refractory to medical therapy and IABP placement, placement of a left ventricular assist device (LVAD) should be considered. A ventricular assist device should only be placed in those patients in whom the cardiogenic shock is deemed to be reversible or if it is being used as a bridge option.

The hemodynamic effects of LVAD are superior to those of IABP:

• ↑ cardiac output
• ↑ mean arterial pressure
• ↓ pulmonary capillary wedge pressure
• ↓ central venous pressure
• ↓ pulmonary arterial pressure
• ↓ filling pressures in the left and right ventricle
• ↓ myocardial oxygen demand

Despite the superiority of hemodynamic support of LVAD compared to IABP, the use of LVAD is limited by the high risk of complications (such as bleeding), the complexity of insertion, and the absence of data regarding survival benefit. According to a metanalysis of 3 controlled trials (two trials on the TandemHeart and one trial on the Impella device), the use of LVAD was associated with a superior hemodynamic support without a reduction in 30-day mortality (RR=1.06, 95% CI 0.68–1.66).

Extracorporeal Membrane Oxygenation (ECMO)

Hemodynamic effects of extracorporeal membrane oxygenation (ECMO):

• ↓ left ventricular preload
• ↑ left ventricular afterload
• ↑ myocardial oxygen demand

ECMO use is associated with complications such as bleeding, renal failure, and systemic inflammatory response syndrome.

Urgent Revascularization

If the patient has an ST elevation myocardial infarction complicated by cardiogenic shock, then primary angioplasty should be performed to restore flow to the culprit artery irrespective of time delay since the onset of symptoms (Class I, level of evidence B). Consideration should also be given to restoration of flow in the non-culprit territories in the setting of cardiogenic shock. Patients with MI complicated by cardiogenic shock who initially present to a hospital where PCI is not available should be urgently transferred to another PCI-capable healthcare facility (Class I, level of evidence B). Urgent revascularization is a priority over hemodynamic monitoring in MI patients with cardiogenic shock and should not be delayed.

Urgent revascularization can be achieved through one of the following:

• Percutaneous coronary intervention (PCI)
• Coronary artery bypass graft (CABG)
• Fibrinolytic therapy

PCI is the first line revascularization strategy among MI patients with cardiogenic shock. CABG in the setting of cardiogenic shock is associated with high rates of mortality and morbidity, therefore if primary angioplasty can be performed successfully, CABG is preferably avoided. When PCI or CABG can not be perfomed, fibrinolytic therapy is indicated in the absence of any contraindications.

Hemodynamic Monitoring and Stabilization

Hemodynamic Monitoring

The aim of hemodynamic monitoring is to assess the response to treatment and monitor and guide the doses of the inotropes and vasopressors.

Target endpoints are:

• Mean arterial pressure (MAP) of 60 to 65 mmHg
• SaO2 >92%
• SvO2 >60%
• ScvO2 >70%
• Urine output >0.5 mL/kg/h
• Lactate <2.2 mM/L
• Hematocrit ≥30%

Shown below is a table summarizing the different parameters of hemodynamic monitoring, their target goals, and action items needed to achieve these goals.

Preload	Afterload			Cardiac index
Goal: PCWP 15–18 mm Hg, CVP 8–12 cm H2O	Goal: MAP >65 mm Hg, SVR 800–1200 dyn·s·cm−5			Goal: CI >2.2 L/min/m2
Fluid challenge protocol ("TROL") ± Correct pulmonary congestion Furosemide Usual dose: 40 mg slow IV injection May increase dose to 80 mg after 1 hour as needed Morphine Usual dose: 2–4 mg slow IV injection May repeat dose every 5–30 minutes as needed	If ↑ MAP & ↑ SVR: Taper vasopressor ± Vasodilator Nitroglycerin Initial dose: 5.0 μg/min Titrate by 10–20 μg/min q 3–5 min Nitroprusside Initial dose: 0.3 μg/kg/min Usual dose: 3.0–5.0 μg/kg/min Maximum dose: 10 μg/kg/min	If ↓ MAP & ↓ SVR: Vasopressor Norepinephrine Initial dose: 0.5–1.0 μg/min Maximum dose: 30–40 μg/min Titrate to SBP >90 mm Hg Dopamine Cardiac dose: 5.0–10 μg/kg/min Pressor dose: 10–20 μg/kg/min Maximum dose: 20–50 μg/kg/min Phenylephrine Initial dose: 100–180 μg/min Maintenance dose: 40–60 μg/min ± Vasopressin Adjunctive therapy to norepinephrine or dopamine Usual dose: 0.01–0.03 U/min Maximum dose: 0.04 U/min	If ↓ MAP & ↑ SVR: Continue vasopressor Optimize cardiac output with inotropic agent	Dobutamine Usual dose: 2.0–20 μg/kg/min Maximum dose: 40 μg/kg/min Avoid ↑ HR by >10% of baseline Milrinone Loading dose: 50 μg/kg (slowly over 10 minutes) Maintenance dose: 0.375–0.75 μg/kg/min

Volume Management

The goal of managing the patient with cardiogenic shock is to optimize the filling of the left ventricle so that the Starling relationship and mechanical performance and contractility of the heart is optimized. In the setting of acute MI, a pulmonary capillary wedge pressure of 18 to 20 mm Hg may optimize left ventricular filling. Filling pressures higher than this may lead to LV dilation, and poorer left ventricular function.

Even though, there is adequate intravascular volume in cardiogenic shock, fluid administration should be considered in patients with cardiogenic shock following acute MI because patients are often diaphoretic with subsequent relative hypovolemia.

Contraindicated Medications

Cardiogenic shock is considered an absolute contraindication to the use of the following medications:

• Acebutolol
• Amiodarone
• Atenolol
• Betaxolol
• Bisoprolol
• Brimonidine tartrate and Timolol maleate
• Carvedilol
• Disopyramide
• Esmolol
• Metoprolol
• Mexiletine
• Nadolol
• Nesiritide
• Penbutolol
• Pindolol
• Propafenone
• Propranolol
• Sotalol
• Timolol
• Verapamil
• Labetalol

2013 Revised ACCF/AHA Guidelines for the Management of ST-Elevation Myocardial Infarction (DO NOT EDIT)

General and Specific Considerations (DO NOT EDIT)

Class I

"1. Primary PCI should be performed for patients less than 75 years old with ST elevation or presumably new left bundle-branch block who develop shock within 36 hours of MI and are suitable for revascularization that can be performed within 18 hours of shock, unless further support is futile because of the patient’s wishes or contraindications/unsuitability for further invasive care. (Level of Evidence: A)"

"7. Primary PCI should be performed in patients with STEMI and cardiogenic shock or acute severe HF, irrespective of time delay from myocardial infarction (MI) onset. (Level of Evidence: B)"

Class IIa

"1. Primary PCI is reasonable for selected patients 75 years or older with ST elevation or left bundle-branch block or who develop shock within 36 hours of MI and are suitable for revascularization that can be performed within 18 hours of shock. Patients with good prior functional status who are suitable for revascularization and agree to invasive care may be selected for such an invasive strategy. (Level of Evidence: B)"

Treatment of Cardiogenic Shock in Patients with STEMI (DO NOT EDIT)

Class I

"1. Emergency revascularization with either PCI or CABG is recommended in suitable patients with cardiogenic shock due to pump failure after STEMI irrespective of the time delay from MI onset. (Level of Evidence: B)"

"2. In the absence of contraindications, fibrinolytic therapy should be administered to patients with STEMI and cardiogenic shock who are unsuitable candidates for either PCI or CABG. (Level of Evidence: B)"

Class IIa

"1. The use of intra-aortic balloon pump counterpulsation can be useful for patients with cardiogenic shock after STEMI who do not quickly stabilize with pharmacological therapy. (Level of Evidence: B)"

Class IIb

"1. Alternative left ventricular (LV) assist devices for circulatory support may be considered in patients with refractory cardiogenic shock. (Level of Evidence: C)"

References

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