Ju H. Kim, MD, et al. Nucleic Acid Delivery for Endothelial Dysfunction in Cardiovascular Diseases. Methodist DeBakey Cardiovascular Journal. 2020;16(1):1-70.
Cardiogenic shock (CS) is a complex condition characterized by end-organ hypoperfusion and requiring pharmacologic and/or mechanical circulatory support. It is caused by a decline in cardiac output due to a primary cardiac disorder. CS is frequently complicated by multiorgan system dysfunction that requires a multidisciplinary approach in a critical care setting. Appropriate use of diagnostic data using tools available in a modern cardiac intensive care unit should guide optimal management incorporating both pharmacologic and nonpharmacologic therapies to minimize morbidity and mortality.Keywords
cardiogenic shock, critical care, acute myocardial infarction, heart failure, pulmonary artery catheterization
Cardiogenic shock (CS) is a complex condition characterized by end-organ hypoperfusion due to a decline in cardiac output resulting from a primary cardiac disorder. Clinically, CS can present with a broad spectrum of hemodynamic phenotypes. However, the unifying characteristic is inadequate cardiac output requiring pharmacologic and/or mechanical circulatory support.
CS is a leading indication for admission to a contemporary cardiac intensive care unit (CICU). Investigators with the Critical Care Cardiology Trials Network characterized the demographics, diagnoses, and outcomes of more than 3,000 consecutive admissions to tertiary CICUs across the United States and Canada and found that the primary indications for CICU care were respiratory insufficiency (26.7%) and shock (21.1%).1 Intravenous vasoactive medications, invasive hemodynamic monitoring, and mechanical ventilation were required in 58.2% of patients, and those admitted with CS had a 30.6% mortality rate.1 The presence of acute noncardiovascular illnesses such as acute kidney injury or acute respiratory failure has been associated with increased in-hospital mortality and longer length of stay in the CICU.2
Optimal management of CS in the CICU first requires careful investigation into its etiology. The most common causes of CS remain acute myocardial infarction followed by acute on chronic heart failure (Table 1). Diagnostic and managementstrategies for these specific etiologies of CS are reviewed elsewhere in this issue. Regardless of the etiology, CS is frequentlycomplicated by multiorgan system dysfunction that requires a multidisciplinary approach to care in an intensive care setting.Initial goals of treatment are to achieve euvolemia and hemodynamic stabilization to optimize end-organ perfusion to avoid or minimize multiorgan system dysfunction. Prevention and management of multiorgan system dysfunction is paramount to achieve favorable outcomes in CS. In a retrospective cohort study over a 15-year period (2000-2014), Vallabhajosyula and colleagues found that 31.9% of admissions for CS due to acute myocardial infarction were complicated by multiorgan failure.The presence of multiorgan failure was associated with an odds ratio of 2.23 (95% CI, 2.19-2.27) for higher in-hospital mortality, greater resource utilization, and fewer discharges to home.3
Given its complexity and associated high mortality rate, management of CS demands accurate identification of the hemodynamic phenotype as well as a collaborative multidisciplinary approach to optimize pharmacologic and nonpharmacologic therapies. Here we review practical considerations for management of CS in the critical care setting.
ROLE OF PULMONARY ARTERY CATHETERIZATION IN CS
Hemodynamic instability and metabolic derangements are inherent in the pathophysiology of CS. Therefore, invasive monitoring of not only systemic arterial pressures but also measures of end-organ perfusion are important to properly identify the etiology of the shock state. The pulmonary artery (PA) catheter is a vital diagnostic tool widely available in a critical caresetting that can aid in appropriate identification of the presence and type of CS as well as guide therapy.
The concept of cardiac catheterization was first introduced in 1929 when Werner Forssmann introduced a catheter into his own heart and proved that it was feasible. Since then, many iterations of catheters have been developed that can be introduced into the right side of the heart and measure pressure in pulmonary arteries.4-6 However, it was Drs. William Ganz and H.J.C.Swan who developed the floating balloon-tipped PA catheter in 1970 that could be inserted at the bedside without the use of fluoroscopy.7 Since its first iteration, the Swan-Ganz catheter has undergone further modifications including the placement of athermistor coil for measurement of cardiac output by thermodilution, infusion ports for drug delivery, and pacing function for right ventricular pacing.
The routine use of Swan-Ganz catheters in clinical practice in acutely ill patients in an ICU has been controversial. Early after its introduction, the catheter was widely adopted and used especially in patients post myocardial infarction (MI) for hemodynamic monitoring. Although instrumental in understanding the hemodynamics in acute MI patients, their routine use came with its own set of adverse events. In 1987, Gore et al. reported in a retrospective observational study that PA catheterswere associated with increased mortality and morbidity in patients with acute MI and hypotension and/or congestive cardiac failure.8 These results prompted further randomized clinical trials examining the utility of PA catheters. Several studiesperformed in high-risk surgical patients and those with acute lung injury showed that use of PA catheters in these populations was associated with increased mortality.9-11
The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trialwas conducted in hospitalized patients with decompensated chronic heart failure. This trial randomized patients to therapy guided by clinical assessment in conjunction with the PA catheter versus clinical assessment alone. ESCAPE showed nodifference in mortality between the two groups. Moreover, use of the PA catheter in this trial was associated with more adverse events.12 However, ESCAPE has been criticized for its multiple potential confounders, including the possibility that appropriate use in CS patients in particular may have shown overall benefit.
A retrospective cohort study conducted by Hernandez and colleagues showed that although use of PA catheters hasdeclined over the past decade, its use in patients admitted with CS was associated with lower mortality.13 Rossello et al. also reported lower short- and long-term mortality associated with using a PA catheter in patients with CS.14 Use of PA cathetersalso allows for continuous evaluation of the hemodynamic response to therapeutic manipulations to optimize filling pressuresand cardiac output. However, their use does carry risks for procedural complications, infections, pulmonary infarction, pulmonary hemorrhage, and the potential for inaccurate data collection and interpretation.15 Therefore, invasive hemodynamic monitoring should be incorporated to complement clinical assessment and other available markers of tissue perfusion such asmeasures of arterial lactate, kidney and liver function, mental status, and urine output.
Initial pharmacologic management of CS should include a review of the medications and discontinuing those that may becontributing to hypotension and negative inotropy. For example, in patients on guideline-directed medical therapy (GDMT) for chronic heart failure, this may require discontinuation of all or part of their GDMT regimen. Discontinuation of GDMT in this population portends a worse prognosis. Compelling data from the OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) registry show that beta blocker withdrawal in patients hospitalized for acutely decompensated heart failure is associated with worse mortality (HR: 2.3; 95% CI, 1.2-4.6, P = .013).16 Tran and colleagues assessed over 5,000 patients admitted for acute decompensated heart failure and found that patients who had GDMT discontinued during the hospital admission had increased mortality (HR 1.30; 95% CI, 1.02-1.66).17 In patients with CS due to acute MI, early initiation of beta blockers and renin-angiotensin-aldosterone system inhibitors prior to complete resolution of CS was associated with an increased 30-day mortality.18
INOTROPES AND VASOPRESSORS
Inotropes increase the cardiac contractility and output in CS. Vasopressors increase vascular tone and therefore augmentsystemic vascular resistance to increase blood pressure. Commonly used vasopressors and inotropes are outlined in Table 2. Dobutamine and milrinone are the main inotropes used in a contemporary CICU, and both result in increased myocardial contractility albeit through different mechanisms. Norepinephrine, epinephrine, dopamine, and vasopressin are commonly used vasopressors in cases of CS with hypotension. Despite their widespread availability, a Cochrane meta-analysis of inotropes and vasopressor use in CS did not find conclusive evidence to recommend one particular agent over another.19 The American Heart Association (AHA) consensus scientific statement on the management of CS also notes that insufficient evidence existsto guide the selection of pharmacologic therapies.20 Therefore, use of inotropic and vasopressor agents should be guided by available hemodynamic data and clinician judgment.
Dobutamine is a nonselective β1, β2, and α1 agonist that stimulates the G-protein adenylate cyclase cascade, resulting in increased cyclic AMP production and ultimately increased calcium uptake. This results in an increase in cardiac output due to increased heart rate and stroke volume. The affinity for β1 is highest, causing increased chronotropy and inotropy; at dosesused for maintenance therapy (< 10 mcg/kg/min), the mild β2 and α1 agonism balance out, causing little to no change insystemic vascular resistance.21 The resulting augmentation in cardiac output is beneficial in CS but should be balanced against the risk of developing tachyarrhythmia and increasing myocardial oxygen consumption.22
Milrinone is a selective phosphodiesterase-3 inhibitor that causes an increase in intramyocyte cyclic adenosine monophosphate and resultant calcium uptake in the sarcoplasmic reticulum. Due to its indirect impact on β cells, milrinone hasmore inotropic than chronotropic effects. It causes vasodilation of both the systemic and pulmonary vasculature and has beenshown to produce an equivalent reduction in pulmonary vascular resistance as sildenafil but a greater reduction in pulmonary capillary wedge pressure.23 As a result, milrinone augments cardiac output by increasing stroke volume and heart rate but also decreases systemic vascular resistance. Milrinone has a significantly longer half-life compared to dobutamine at 90 minutes,which is further prolonged in renal dysfunction.
There is a paucity of randomized clinical trial data to clearly conclude the effects of inotropes on clinical outcomes. The data with dobutamine has demonstrated that there is an improvement in symptoms and initial hemodynamic profile; however, both short- and long-term mortality appear to increase with dobutamine. The FIRST (Flolan International RandomizedSurvival Trial) study demonstrated an increased mortality in patients treated with dobutamine at 6 months when compared to those without (70.5% vs 37.1%, P = .0001).24 However, this was a subgroup analysis of a study assessing the effects of intravenous epoprostenol on patients with advanced heart failure. The patients on dobutamine tended to be sicker with more advanced heart failure, which may have impacted the results. More recently, when dobutamine was compared to levosimendanin the SURVIVE (Survival of Patients with Acute Heart Failure in Need of Intravenous Inotropic Support) trial, there was no difference in mortality between the two agents.25 The overall mortality rates attributed to dobutamine at 30, 90, and 180 dayswere 14%, 21%, and 26%, respectively, lower than those seen in the FIRST trial.25 One potential mechanism for the increased mortality associated with dobutamine is thought to be cardiac arrhythmias and increased myocardial oxygen demand leading to ischemia. The rates of implantable cardiac defibrillators (ICD) were not reported in either the FIRST or SURVIVE trials. It isunclear if a higher rate of ICD use contributed to the lower mortality seen in the more current SURVIVE trial.
In the OPTIME-CHF (Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure) trial that studied the effect of milrinone in those with decompensated heart failure, milrinone demonstrated no improved in-hospital or 60-day mortality over placebo but was associated with significantly more arrhythmias (8% vs 3%) and hypotension (10.7% vs 3.2%).26 Milrinone does not work directly through the adrenergic system; therefore, it is preferable to use in patients who are able to tolerate remaining on beta blocker therapy because it has less effect on cardiac index.21
The 2013 American College of Cardiology/AHA guidelines for the management of chronic heart failure give inotropes aclass I recommendation to be used in patients with CS until definitive therapy can be performed.27 The use of inotropes for hospitalized patients with acute decompensated heart failure with hypotension and signs of decreased perfusion as well aspalliative use for symptom relief in patients ineligible for advanced therapies has a class IIa recommendation.
The Acute Decompensated Heart Failure National Registry (ADHERE) evaluated patients admitted for acute decompensated heart failure and found that, despite similar baseline characteristics, patients who received dobutamine or milrinone had a significantly higher in-hospital mortality than patients who received vasodilator therapy with nitroglycerin ornesiritide (13.9%, 12.3%, 4.7%, and 7.1% respectively).28 While symptoms and initial hemodynamic parameters may improve with the use of inotropes, their potential impact on mortality is not trivial. Careful patient selection and close monitoring are imperative to take advantage of the benefits while minimizing exposure to the adverse effects.
When hypotension occurs in CS, the use of vasopressors is required to maintain normotension and provide adequate end-organ perfusion. In the SOAP II (Sepsis Occurrence in Acutely Ill Patients) trial, norepinephrine was compared to dopamine in patients with shock due to various etiologies.29 There was no difference in mortality between dopamine and norepinephrine in the overall cohort, but there were significantly more arrhythmias seen with dopamine (24.1% vs 12.4%, P < .001). In thesubgroup of patients with CS, dopamine was associated with an increased mortality compared to norepinephrine; however, thiswas a subgroup analysis so it should be interpreted with caution.29 Recently, Levy and colleagues evaluated the use of norepinephrine and epinephrine in CS secondary to acute myocardial infarction.30 The authors found that compared with epinephrine, norepinephrine was associated with an insignificantly lower death rate at 7 days (30% vs 10%) and during the course of hospital admission (52% vs 37%). Use of norepinephrine was also associated with a statistically significant lowerrate of refractory shock (37% vs 7%, P = .01).30 Similar results were seen in the observational CardShock study, in whichepinephrine was associated with an increase in 90-day mortality compared with other vasopressors (OR 5.2, 95% CI, 1.88,14.7, P = .002).31 The mechanism for increased mortality is thought to be due to increased myocardial oxygen consumption, excessive vasoconstriction, and direct toxic effect on end organs.
Dopamine is a nonselective agent that affects different receptors depending on the dose. Doses below 4 mcg/kg/min have been termed “renal dose” because the dopamine receptors are activated, which results in vasodilation of splanchnic and renal vessels that theoretically increases renal blood flow. Several studies have examined the effects of dopamine on renal function in patients with heart failure, the largest being the ROSE AHF (Renal Optimization Strategies Evaluation in Acute Heart Failure) trial.21,32 In patients admitted for acute heart failure with moderate renal dysfunction, low-dose dopamine at 2 mcg/kg/min resulted in no improvement in urine output, serum creatinine, or patient-perceived symptoms, and there was significant discontinuation due to tachycardia (7.2%).32 In the SOAP II trial, the median dose was 10 mcg/kg/min, which predominantly affects α and β receptors, causing vasoconstriction and positive inotropy. The reason for increased mortality in the CS subgroup is not elucidated. Moreover, the etiology or management of CS was not reported. Ventricular arrhythmiasonly accounted for 1.5% of the 12.4% reported, so sudden cardiac death was not the cause of increased mortality.29
Pharmacologic armamentarium for CS include both inotropic agents to increase cardiac output and vasopressors when needed for hypotension. Unfortunately, none of these therapies have been shown to improve mortality. Cases of CS refractory to pharmacologic therapy require escalation to temporary mechanical circulatory support devices, which is reviewed elsewhere in this issue.
ROLE OF NONPHARMACOLOGIC THERAPIES
Adjunctive nonpharmacologic therapies have a role in the critical care management of CS. Acute heart failure and CS are often characterized by increased intracardiac filling pressures due to sodium and fluid retention by the kidneys resulting fromneurohormonal activation. Diuretics are the mainstay of therapy to reduce congestion. However, impaired absorption, decreased renal blood flow, and proteinuria can lead to diuretic resistance. In turn, worsening congestion can lead tomultiorgan dysfunction, including acute renal failure, which further propagates this vicious cycle.33 Acute right ventricular failure can also manifest with worsening congestion associated with right ventricular distention, increased ventricularinterdependence, decreased left ventricular filling, and worsening of shock and end-organ failure.34 In such situations, ultrafiltration may be a viable option to decrease vascular congestion.
Ultrafiltration describes the process of solvent-free fluid transport across a semipermeable membrane driven by the pressure gradient across the membrane. Ultrafiltration can be used in isolation to achieve volume control or can be combined with diffusion, as is done with dialysis to achieve both solute and volume control.35 With the development of newer simplified devices, ultrafiltration can be achieved with minimal extracorporeal volume, thus minimizing hemodynamic instability.
In theory, ultrafiltration appears advantageous over pharmacologic diuresis because it does not lead to neurohumoral activation, significant hypokalemia, or hypomagnesemia, and the rate and amount of fluid removed can be precisely controlled.Several randomized trials were conducted to assess the benefit of ultrafiltration over diuretics. Although some of the trialsshowed greater reduction in heart failure symptoms and weight loss with ultrafiltration compared to diuretics,36,37 the resultswere not consistent across all the trials. A greater increase in serum creatinine was seen, reflecting possible renal tubular injuryand other adverse effects, thereby questioning the benefit of ultrafiltration over diuretics.38,39 Unfortunately, these trialsexcluded patients on inotropic or vasoactive agents, effectively excluding patients in CS. Currently, there are no large randomized trial data to test the benefit of ultrafiltration in CS. In a retrospective study conducted by Li et al. among post-cardiac surgery patients in CS with acute kidney failure, continuous venovenous hemofiltration was associated with better in-hospital and long-term survival.40
Mechanical ventilation may be required in cases of CS due to acute hypoxemia, increased work of breathing, decreased level of consciousness requiring airway protection, or overall hemodynamic instability. Despite the high prevalence of respiratory failure requiring mechanical ventilation, there is a paucity of data to support a particular mode of ventilation or physiologic targets for oxygenation or ventilation in CS. Clinicians must be mindful of the interactions between positive pressure ventilation on left and right ventricular hemodynamics as well as the optimal agents for analgesia and sedation in CS.
CS is a complex heterogeneous disorder of ineffective cardiac output associated with high mortality and often complicated by multiorgan system dysfunction. Rapid identification of the etiology of CS aided by invasive hemodynamic data are critical to optimal management. The lack of high-quality data in the field of CS demands coordination of care across multiple disciplines in order to improve patient outcomes. Management of CS remains a high research priority to address the multiple gaps in knowledge.
- Cardiogenic shock (CS) is a complex heterogeneous disorder of inadequate end-organ perfusion caused by inadequate cardiac output and is associated with a high mortality rate.
- CS is frequently complicated by multiorgan system dysfunction that requires a multidisciplinary approach using both pharmacologic and nonpharmacologic therapies.
- Limited data exist to guide the selection of pharmacologic therapies for CS. Therefore, clinical judgment and appropriate application of hemodynamic data are critical to improve patient outcomes.
The authors have completed and submitted the Methodist DeBakey Cardiovascular Journal Conflict of Interest Statement and none were reported.
Cardiovascular Implications of COVID-19 Infections
Thakkar AN, Tea I, Al-Mallah MH. Cardiovascular Implications of COVID-19 Infections. Methodist DeBakey Cardiovasc J. Published online May 28, 2020.
Pathophysiology and Advanced Hemodynamic Assessment of Cardiogenic Shock
Brener MI, Rosenblum HR, Burkhoff D. Pathophysiology and Advanced Hemodynamic Assessment of Cardiogenic Shock. Methodist DeBakey Cardiovasc J. 2020;16(1):7-15.
Cardiogenic Shock in the Setting of Acute Myocardial Infarction
Kapur NK, Thayer KL, Zweck E. Cardiogenic Shock in the Setting of Acute Myocardial Infarction. Methodist DeBakey Cardiovasc J. 2020;16(1):16-21.