A Standardized and Comprehensive Approach to the Management of Cardiogenic Shock

Abstract

Cardiogenic shock is a hemodynamically complex syndrome characterized by a low cardiac output that often culminates in multiorgan system failure and death. Despite recent advances, clinical outcomes remain poor, with mortality rates exceeding 40%. In the absence of adequately powered randomized controlled trials to guide therapy, best practices for shock management remain nonuniform. Emerging data from North American registries, however, support the use of standardized protocols focused on rapid diagnosis, early intervention, ongoing hemodynamic assessment, and multidisciplinary longitudinal care. In this review, the authors examine the pathophysiology and phenotypes of cardiogenic shock, benefits and limitations of current therapies, and they propose a standardized and team-based treatment algorithm. Lastly, they discuss future research opportunities to address current gaps in clinical knowledge.

In 1967, Drs. Killip and Kimball reported a nearly 4-fold decline in acute myocardial infarction (AMI) mortality utilizing continuous monitoring for post-infarction arrhythmias (1). Unfortunately, patients who developed cardiogenic shock (CS) still fared poorly, with in-hospital mortality of 81%. It was not until 1999 that the landmark SHOCK (Should We Emergently Revascularize Occluded Arteries in Cardiogenic Shock) trial demonstrated improvement in AMI-CS survival (2). More than 2 decades later, short-term mortality from CS still remains >40% (3). Recent North American registries, however, suggest that outcomes may be improved through early shock recognition and standardized treatment algorithms (4–6). In this review, we discuss the pathophysiology and classification of CS and propose a standardized approach to care, from diagnosis to discharge (Central Illustration).

CENTRAL ILLUSTRATION. Proposed Pathway for Contemporary Shock Care.

Schematic representation of a proposed pathway for cardiogenic shock (CS) management. Key components include timely recognition, early invasive hemodynamics and selective and tailored circulatory support. Regionalized systems of care with multidisciplinary CS teams can aid in the triage and transfer of these patients to dedicated Level 1 CS centers for full spectrum and longitudinal care. ADHF-CS = acute decompensated heart failure complicated by cardiogenic shock; AMI-CS = acute myocardial infarction complicated by cardiogenic shock; CI = cardiac index; CICU = cardiac intensive care unit; CPO = cardiac power output; IABP = intra-aortic balloon pump; PAPi = pulmonary arterial pulsatility index; PCWP = pulmonary capillary wedge pressure; SBP = systolic blood pressure; VA-ECMO = venoarterial extracorporeal membrane oxygenation.

EPIDEMIOLOGY AND ECONOMIC IMPACT

CS is estimated to complicate 5% to 12% of AMIs (3). With an aging population, CS incidence is on the rise, and patients are increasingly complex, with more associated comorbidities (7). Although even small ischemic insults may precipitate shock in patients with pre-existing myocardial dysfunction, AMI-CS is typically associated with >40% loss of left ventricular (LV) myocardium (8). Mechanical complications such as free wall rupture, ventricular septal defect, and papillary muscle rupture may also precipitate AMI-CS (9). CS may additionally occur in patients with heart failure due to longstanding ventricular dysfunction (acute decompensated heart failure with CS [ADHF-CS]). This form of CS often follows an indolent clinical course and is more likely to require a biventricular hemodynamic support compared with AMI-CS (10). Post-cardiotomy CS complicates 0.1% to 0.5% of cardiac surgeries, because of pre-existing myocardial dysfunction or intraoperative complications, including inadequate myocardial protection, acute bypass graft failure, prosthetic valve dysfunction, pericardial effusion, or aortic dissection (11).

The economic impact of CS is substantial, especially when accompanied by multiorgan system failure, which is associated with nearly 50% in-hospital mortality, longer lengths of stay, and greater resource utilization (12). Analysis of 444,253 AMI-CS admissions from the National (Nationwide) Inpatient Sample from 2000 to 2014 observed a 4.3-fold increased risk of developing multiorgan system failure. Overall, the annual cost of CS exceeds $65 million (12,13), and survivors face impaired quality of life with higher rates of immobility, depression, and chronic anxiety (14).

PATHOPHYSIOLOGY

The central pathophysiologic derangement in CS is diminished cardiac output (CO) (3), leading to systemic hypoperfusion and maladaptive cycles of ischemia, inflammation, vasoconstriction, and volume overload, often culminating in multiorgan system failure and death (Figure 1) (3,15). The initial cardiac insult may stem from various etiologies (Table 1). Impaired CO and progressive diastolic dysfunction raise ventricular end-diastolic pressures, which reduce coronary perfusion pressure, myocardial contractility, and stroke volume (3). In response to tissue ischemia and necrosis, released inflammatory mediators further impair tissue metabolism and induce nitric oxide production, which causes systemic vasodilation and exacerbates hypotension (16), stressing an already dysfunctional myocardium (3). This maladaptive response may be acute, as occurs in AMI-CS, or superimposed on chronic neurohormonal activations that accompany ADHF-CS. Hypoxia and pulmonary inflammation induce pulmonary vasoconstriction, increasing biventricular afterload and myocardial oxygen demand. The renal response to impaired glomerular perfusion increases tubular sodium reabsorption and activation of the renin-angiotensin-aldosterone axis, resulting in further volume overload and compromised diuretic effectiveness. Sympathetically mediated splanchnic vasoconstriction further worsens volume overload by redistributing 50% of total blood volume back to the circulation (17). Augmented ventricular filling pressures further worsen myocardial efficiency and ischemia, especially within the right ventricle (RV) (18). Left unabated, this maladaptive cycle often progresses to death.

FIGURE 1. Pathophysiology of Cardiogenic Shock.

Cardiogenic shock is a Low-output state stemming from primary cardiac dysfunction, resulting in hypotension and systemic hypoperfusion. This maladaptive syndrome is perpetuated by physiologic cycles of inflammation, ischemia, vasoconstriction, and volume overload.

TABLE 1.

Common Etiologies of Cardiogenic Shock

Left ventricular failure • Acute myocardial infarction • Hypertrophic obstructive cardiomyopathy • Myocarditis • Myocardial contusion • Peripartum cardiomyopathy • Post-cardiotomy • Progressive cardiomyopathy • Septic cardiomyopathy • Stress cardiomyopathy (takotsubo) • Ventricular outflow obstruction Right ventricular failure • Acute myocardial infarction • Myocarditis • Post-cardiotomy • Progressive cardiomyopathy • Pulmonary embolism • Septic cardiomyopathy • Worsening pulmonary hypertension

Arrhythmia • Atrial fibrillation or flutter • Ventricular tachycardia or fibrillation • Bradycardia or heart block Pericardial disease • Tamponade • Progressive pericardial constriction Chemotherapeutic, toxic, metabolic • Calcium-channel antagonists • Adrenergic receptor antagonists • Thyroid disorders Valvular or mechanical dysfunction • Aortic regurgitation—acute bacterial Endocarditis • Mechanical valve dysfunction or thrombosis • Mitral regurgitation—myocardial ischemia or Infarction • Progressive mitral stenosis • Progressive aortic stenosis • Ventricular septal defect or free wall rupture

DEFINITION AND CLASSIFICATION

Clinical trials and societal guidelines have employed a variety of definitions of CS (2,19–23). Patient eligibility for the SHOCK trial (2) was based on both clinical and hemodynamic criteria, whereas other trials relied on clinical criteria, including sustained hypotension and evidence of end-organ malperfusion (Table 2). Building on the Diamond-Forrester classification system using cardiac index and pulmonary capillary wedge pressure, CS profiles initially focused on pulmonary congestion and systemic perfusion (24). Modern CS phenotyping is more nuanced, encompassing a broader spectrum of clinical and hemodynamic presentations beyond the classic “cold and wet” construct. Phenotypes of CS may include LV-dominant, RV-dominant, and biventricular profiles, each with its own unique hemometabolic characteristics (25). Patients may also present in preshock, in which compensatory vasoconstriction may maintain a near-normal systolic blood pressure despite malperfusion, sometimes falsely reassuring physicians (25,26). Although comprising only 5.2% of the SHOCK trial registry, these normotensive and hypoperfused patients represented a high-risk cohort with lower average CO compared with hypotensive patients with CS and a 43% in-hospital mortality (27). In search of a common language for defining disease severity, the Society for Cardiovascular Angiography and Interventions (SCAI) recently put forth a 5-stage (A-E) classification system for CS (26). This nomenclature system has been retrospectively validated and correlated to in-hospital and cardiac intensive care unit (CICU) mortality (28).

TABLE 2.

CS Definitions Used in Clinical Trials

	SHOCK Trial (1999) (2)	IABP-SHOCK II Trial (2012) (22)	IMPRESS Trial (2017) (23)	CULPRIT-SHOCK Trial (2017) (20)
Study design	RCT	RCT	RCT	RCT
Study arms	Emergent revascularization vs. initial medical stabilization in AMI-CS	IABP vs. optimal medical therapy in AMI-CS treated with early revascularization (PCI or CABG)	Impella CP vs. IABP in mechanically ventilated patients with AMI complicated by severe CS	Culprit lesion PCI (with option of staged revascularization) vs. ad hoc multivessel PCI in AMI-CS with multivessel CAD
Sample size	302	600	48	786*
Clinical criteria	• SBP <90 mm Hg for ≥30 mins OR vasopressors to maintain SBP ≥90 mm Hg AND • End-organ hypoperfusion (urine output <30 ml/h or cool extremities)	• Sustained SBP <90 mm Hg for ≥30 min or catecholamines to maintain SBP >90 mm Hg AND • Clinical pulmonary congestion AND • Impaired end-organ perfusion with ≥1 of the following criteria:  a) Altered mental status  b) Cold/clammy skin and extremities  c) Urine output <30ml/h  d) Lactate >2.0 mmol/l	• Sustained SBP ≥90 mm Hg for >30 min or need for vasopressors/inotropes to maintain SBP >90 mm Hg	• Sustained SBP ≥90 mm Hg for >30 min or need for vasopressors/inotropes to maintain SBP>90 mm Hg • Clinical pulmonary congestion • Impaired end-organ perfusion with ≥1 of the following criteria:  a) Altered mental status  b) Cold/clammy skin and extremities  c) Urine output <30 ml/h  d) Lactate >2.0
Hemodynamic criteria	• CI ≤2.2 l/min/m2 and PCWP >15 mm Hg	–	–	–

^*Data was evaluated for 686 patients.

AMI = acute myocardial infarction; CABG = coronary artery bypass grafting; CAD = coronary artery disease; CI = cardiac index; CS = cardiogenic shock; CULPRIT-SHOCK = Culprit Lesion Only PCI versus Multi-vessel PCI in Cardiogenic Shock; IABP = intra-aortic balloon pump; IABP-SHOCK II = Intraaoartic Balloon Pump in Cardiogenic Shock II; IMPRESS in Severe Shock = IMPella versus IABP Reduces mortality in STEMI patients treated with primary PCI in Severe cardiogenic SHOCK; PCI = percutaneous coronary intervention; NA = not applicable; PCWP = pulmonary capillary wedge pressure; RCT = randomized controlled trial; SBP = systolic blood pressure; SHOCK = Should We Emergently Revascularize Occluded Arteries in Cardiogenic Shock.

MANAGEMENT OF CS

EMERGENCY DEPARTMENT CARE.

Effective emergency department triage is key to the early recognition and treatment of CS. In AMI-CS, this means timely acquisition and interpretation of a 12-lead electrocardiogram by emergency medical personnel and immediate transfer to a percutaneous coronary intervention (PCI)-capable facility. In the emergency department, CS diagnosis can be facilitated by physical examination, electrocardiography, laboratory evaluation, and (when available) point-of-care echocardiography (29). Although patients with pre-shock may proceed directly to the cardiac catheterization laboratory, those with SCAI stage C or D CS may first necessitate initial stabilization using vasopressor therapy and mechanical ventilation, albeit without significantly delaying reperfusion (30–32). In patients with SCAI stage E or end-stage CS in whom aggressive therapies may be futile, palliative care consultation and discussions with health care surrogates regarding goals of care may be warranted (33).

INVASIVE HEMODYNAMIC MONITORING.

Despite an absence of benefit of routine pulmonary artery catheter (PAC) use for heart failure (34), growing evidence supports the benefit of early invasive hemodynamic assessment in patients with CS (4–6). PAC use may lead to earlier and more accurate identification of the CS phenotype so that medical and device-based therapies may be applied in a tailored fashion. Given these considerations, the routine use of early invasive hemodynamics has been advocated as the standard of care in contemporary CS management (25,31).

VASOACTIVE THERAPIES.

Intravenous inotropes and vasopressors remain fundamental to the acute management of CS. These agents may increase ventricular contractility and CO, reduce filling pressures, and preserve end-organ perfusion (3,15). Existing inotropes exert their physiological effects through the modulation of cardiomyocyte calcium fluxes. Available intravenous inotropic and vasopressor drugs include adrenergic agents (norepinephrine, epinephrine), congeners (dobutamine, dopamine), phosphodiesterase inhibitors (milrinone), and levosimendan, which modulates positive inotropic effects through a combination of calcium sensitization and selective phosphodiesterase-3 inhibition (35,36). Limited data support the use of norepinephrine as the preferred first-line agent, and retrospective analyses suggest similar outcomes with dobutamine and milrinone (30,37). With mechanisms of action independent of the beta-adrenergic receptor, milrinone and levosimendan may be considered to augment CO, especially in patients treated with beta-blockers. Temporizing inotropic support in acute CS has a Class IC indication (38). However, given their propensity to increase myocardial oxygen demand, ischemic burden, and malignant arrhythmias, these agents should be used in the lowest possible doses for the shortest duration (5).

MANAGING CARDIAC ARREST IN CS.

More than 50% of AMI-CS patients suffer concomitant cardiac arrest (CA), either preceding or as a consequence of CS (20,23). The presence of CA increases in-hospital mortality, particularly in the absence of underlying shockable rhythm (39). Given that anoxic brain injury remains the leading cause of mortality in out-ofhospital patients with CA, treatment algorithms based on electrocardiogram findings and the presence or absence of unfavorable clinical features have been proposed to identify patients who might benefit from early angiography (40). In the setting of dynamic and time-dependent complexities associated with AMI-CS complicated by CA, a multidisciplinary approach to management is recommended with emphasis on evaluation of the patient’s overall prognosis, likelihood of a meaningful neurological recovery and candidacy for revascularization and device-based therapies. The potential role for extracorporeal life support in the treatment of AMI-CS patients with refractory CA is of a particular interest, following a single-center study suggesting improved outcomes when employed early in select patients and using a systematic approach (41).

MECHANICAL CIRCULATORY SUPPORT.

Mechanical circulatory support (MCS) devices are increasingly used in CS to stabilize hemodynamics (7) although exactly when, whether, and how to incorporate them in shock care remain controversial (3,15). Potential benefits of MCS include reduction of LV stroke work and intracardiac filling pressures, and enhancement of coronary and end-organ perfusion (42). Device selection should be guided by acuity of illness, CS phenotype, degree of circulatory and ventricular support required, vascular access or anatomy and operator- or center-specific procedural volume and expertise (Figure 2). Understanding how each platform alters ventricular pressure-volume relationships is critical to implementing the optimal strategy (Supplemental Figure) (42). Although axial- and centrifugal-flow devices may improve hemodynamic compared with the intra-aortic balloon pump, no survival benefit has yet been demonstrated (Supplemental Table) (43). In addition, recent observational data from the CathPCI and Chest Pain-MI registries as well as the Premier Healthcare database show wide variations in axial flow device use across the United States and raise safety concerns, in particular major bleeding, stroke, and mortality (44,45). Emerging data from dedicated shock center registries, however, suggest that when MCS devices are deployed selectively using early invasive hemodynamics and standardized multidisciplinary treatment algorithms, improvements in survival may be achieved (4–6). In patients with prohibitive iliofemoral vasculature, expertise in alternative access is key. The axillary artery, in particular, has been demonstrated to be a suitable conduit for intra-aortic balloon pump and Impella (Abiomed, Danvers, Massachusetts) in patients with CS, as it may also facilitate earlier ambulation and improved nutritional status for patients requiring prolonged circulatory support while awaiting cardiac replacement therapy (46,47). Current guidelines provide a Class IIb (Level of Evidence: C) recommendation for utilizing MCS in AMI-CS patients who do not stabilize with pharmacological therapy (48).

FIGURE 2. Current Mechanical Circulatory Support Devices Used for the Treatment of Cardiogenic Shock.

The hemodynamic profiles of the various circulatory support devices available for treatment of cardiogenic shock. ADHF = acute decompensated heart failure; AMI = acute myocardial infarction; AO = aorta; Bi-V = biventricular; CS = cardiogenic shock; FA = femoral artery; FDA = Food and Drug Administration; HR-PCI = high risk percutaneous coronary intervention; IABP = intra-aortic balloon pump; IJ = internal jugular; LA = left atrium; LV = left ventricular; LVAD = left ventricular assist device; PA = pulmonary artery; RA = right atrium; RPM = revolutions per minute; RV = right ventricular; RVF = right ventricular failure; VA-ECMO = venoarterial extracorporeal membrane oxygenation. Adapted with permission from Thiele et al. (15).

Our current practice is to deploy MCS selectively in suitable patients with acute severe or refractory CS after expedited consultation with the multidisciplinary shock team, which consists of an interventional cardiologist, cardiothoracic surgeon, cardiac intensivist, and advanced heart failure specialist. Lactate levels, cardiac power output, and pulmonary arterial pulsatility index help facilitate both MCS selection and weaning strategies. MCS may be utilized as a bridge to myocardial recovery, cardiac replacement therapy, or as a temporizing measure to assess a patient’s candidacy for a durable ventricular assist device or cardiac transplantation. Strict adherence to best vascular access and closure practices, familiarity with device troubleshooting, and multidisciplinary care in a level 1 CICU are critical components of optimal care (49).

CICU MANAGEMENT.

CS is one of the leading indications for CICU admission (50). The care of these patients is inherently resource intensive and complex. Although optimal organizational structure and staffing models continue to be defined, emerging data suggest that “high-intensity” staffing with a dedicated cardiac intensivist or co-management among cardiologists and intensivists may provide more comprehensive, collaborative, and effective critical care delivery (51). As proposed in the 2017 American Heart Association consensus recommendations, CS management in the CICU requires 24/7 care in a level 1 shock center with invasive hemodynamic monitoring and capability to provide comprehensive multiorgan system care (3). Ongoing multidisciplinary shock team consultation may facilitate escalation and weaning strategies in (Figure 3).

FIGURE 3. CICU Management of CS.

This schematic illustrates the longitudinal and multidisciplinary care pathways for cardiogenic shock (CS) care in a contemporary level 1 cardiac intensive care unit (CICU). CI = cardiac index; CO = cardiac output; CPO = cardiac power output; DNR = Do Not Resuscitate order; dPAP = diastolic pulmonary arterial pressure; L = left; MAP = mean arterial pressure; MCS = mechanical circulatory support; PAPi = pulmonary arterial pulsatility index; PCWP = pulmonary capillary wedge pressure; pVAD = percutaneous ventricular assist device; R = right; sPAP = systolic pulmonary arterial pressure; other abbreviations as in Figure 2.

REGIONALIZED SYSTEMS OF CARE.

Comprehensive CS care should ideally be provided at a level 1 center (49). The majority of patients with CS, however, initially present to less well-resourced level 2 centers, which may only offer primary PCI and intra-aortic balloon pump support, or to level 3 centers without PCI capability. Given the demonstrated volume- outcome relationships in CS care, there is a need for regionalized systems of care with shock networks similar to those validated for ST-segment elevation myocardial infarction and trauma (49,52). In this model, emergency medical services and level 2 to 3 centers collaborate in the triage, identification, and stabilization of patients with CS, followed by expedited transfer to a level 1 center using efficient “one-call” communication systems. We direct these referral calls to a single call center that activates the multidisciplinary shock team to render initial treatment recommendations and expedite transfer.

LV ASSIST DEVICES AND HEART TRANSPLANTATION.

Early and ongoing assessment of the potential need for cardiac replacement therapy, either with durable MCS or heart transplantation, is necessary for patients with refractory CS. Therapeutic considerations include conventional risk factors such as age, renal and hepatic function, coagulopathy, aortic valve regurgitation, RV function and medication compliance (54). Thorough clinical and psychosocial evaluation is required. With the updated United Network for Organ Sharing heart allocation protocol prioritizing patients with temporary MCS for expedited heart transplantation, an increasing number of patients with CS have used this pathway (55). Given the high risk of post-transplant mortality in this critically ill patient population, further research is needed to guide patient selection for such advanced therapies (56).

SHOCK RESEARCH.

Ongoing data collection and feedback between physician and administrative champions at hub-and-spoke shock care centers is key to ensuring adherence to best practices, appropriate use of resources, and refinement of system-wide strategies to sustain enhanced outcomes. Such local collaboration may then spur the development of larger multicenter registries and clinical trials on a national level to address clinical gaps in knowledge and assess innovative therapies and care models to inform clinical practice (53).

SPECIAL CONSIDERATIONS FOR AMI-CS

VASCULAR ACCESS.

Transradial access is recommended as the default approach for coronary angiography and PCI in AMI, following clinical trial evidence of reduced major bleeding, vascular complications, and major adverse cardiovascular events compared with transfemoral access (57). It has also been shown to be a viable access site across the severity spectrum of AMI-CS (58). If radial access is not feasible or if MCS is required, safe femoral access techniques should be employed, incorporating combined ultrasound and fluoroscopic guidance, use of micropuncture needles, initial and final runoff angiography, and dedicated hemostasis protocols to avoid vascular complications and bleeding (58).

ANTITHROMBOTIC THERAPIES.

Prompt and potent antithrombotic therapy is paramount in AMI-CS. Several factors, however, pose challenges to achieving prompt and safe antithrombotic effects: 1) delayed absorption of oral P2Y₁₂ inhibitors due to opioid induced enteral dysmotility; 2) impaired cytochrome P450-dependent activation of clopidogrel due to splanchnic and hepatic malperfusion; 3) platelet dysfunction stemming from targeted temperature management and microvascular thrombosis; and 4) bleeding risks associated with large bore access (59). Given limited safety and efficacy data for antithrombotic therapy in AMI-CS, treatment recommendations have been derived from stable AMI populations. These include the preferential use of intravenous unfractionated heparin due to impaired subcutaneous absorption of low-molecular-weight heparin, administration of crushed ticagrelor or prasugrel to effect more rapid and predictable platelet inhibition, and selective administration of the rapid-acting parenteral antiplatelet agent cangrelor to limit the gap in platelet inhibition at the time of PCI (59).

REVASCULARIZATION STRATEGIES.

Although over 70% of patients with AMI-CS present with multivessel coronary artery disease, <4% undergo emergent coronary artery bypass grafting (22). Observational data suggest that PCI and coronary artery bypass grafting share similar mortality rates in AMI-CS (60). Notwithstanding the established benefits of complete revascularization in AMI, the optimal management of non-infarct-related artery lesions in AMI-CS remains unclear (61). To date, the CULPRIT-SHOCK (Culprit Lesion Only PCI versus Multi-vessel PCI in Cardiogenic Shock) trial is the only study to address this question, and demonstrated lower rates of 30-day death or renal replacement therapy with culprit- vessel PCI versus multivessel intervention (20). A recent substudy of the National Cardiogenic Shock Initiative showed comparable mortality, acute kidney injury, and hospital length of stay between the 2 strategies when axial-flow MCS was implanted prior to reperfusion (62), suggesting that revascularization of nonculprit lesions may be feasible when supported by MCS. Ad hoc multivessel PCI in AMI-CS currently receives a Class IIb guideline recommendation (48).

SPECIAL CONSIDERATIONS FOR ADHF-CS AND RV FAILURE

Early elucidation of the primary cause of ADHF-CS, which can account for at least 30% of all CS clinical presentations, is necessary because distinct etiologies respond differently to medical and device-based therapies. In addition to electrocardiography and echocardiography, PAC use facilitates identification of CS phenotype (25). For invasive hemodynamic assessment, the direct Fick method of measuring CO has served as the historic gold standard. However, despite potential limitations (low-output state or severe tricuspid regurgitation), a recent comparison showed thermodilution CO to be superior to estimate Fick measurements (63).

The optimal management of ADHF-CS is predicated on accurate assessment of volume status. The traditional mantra that the RV is preload dependent often leads to inappropriate and detrimental volume loading in the setting of RV dysfunction, which may worsen RV dilation and tricuspid regurgitation. The RV prefers euvolemia with a central venous pressure of 8 to 12 mm Hg (64). RV distention causes leftward interventricular septal shift, compromising LV filling and reducing CO. Diuresis reduces ventricular dilation and improves biventricular coupling (18). In contrast, the RV has less contractile reserve than the more muscular LV, and accordingly, the use of calcitropic agents has been associated with a progressive decline in RV function (65). This may be due, in part, to systemic vasodilation and decreased right-sided perfusion pressures in the setting of elevated RV pressures that accompany pulmonary hypertension. Concomitant use of agents that increase systemic afterload without increasing pulmonary vascular resistance, such as vasopressin or norepinephrine, may be needed to maintain RV perfusion during inodilator therapy, particularly with milrinone (66). In select patients with persistent isolated RV failure refractory to medical therapy, RV MCS may be indicated. Although the Impella RP and Protek Duo (TandemLife, Pittsburgh, Pennsylvania) platforms both bypass the failing RV, the centrifugal pump with Protek Duo allows for splicing of an oxygenator should there also be concomitant respiratory insufficiency (67). RV failure from progressive pulmonary hypertension, however, is poorly treated with devices that only provide RV support, given that the primary lesion is the pulmonary vasculature and forced perfusion may precipitate pulmonary hemorrhage. In these cases, venoarterial extracorporeal membrane oxygenation may be preferred (68).

In select patients with LV-dominant CS and normotensive hypoperfusion, pure vasodilators such as nitroprusside may improve CO by reducing afterload, while the vasodilatory effects of milrinone and dobutamine can also be effective for high-afterload LV failure (3,69). Intravenous or inhaled pulmonary vasodilators reduce RV afterload for pulmonary arterial hypertension and RV failure (70). Minimizing intrathoracic positive pressure ventilation, correcting acidosis, and improving hypoxic pulmonary vasoconstriction may also improve LV filling in the setting of RV failure (18).

CONCLUSIONS

Only recently has the dismal prognosis of CS been significantly altered. However, persistent gaps in knowledge and wide treatment variations continue to hamper progress (Table 3). We propose a standardized approach to CS emphasizing early diagnosis, multidisciplinary care, selective MCS use, and invasive hemodynamics to tailor therapies for CS phenotype. This approach supplemented by dedicated CS shock teams and networks holds promise in improving outcomes. An urgent need for pragmatic randomized clinical trials remains, so that existing and emerging therapies can be adequately evaluated to further inform clinical practice.

TABLE 3.

Opportunities for Future Research in CS Care

Clinical Realms in CS Care	Clinical Gaps in Knowledge	Study Design
1. Diagnosis  a) Pulmonary arterial catheters  b) Classification of CS	• Clinical utility of invasive hemodynamics in CS treatment algorithms • Prospective validation of risk stratification tools	• Prospective multicenter registries • RCT • Prospective multicenter registries
2. Tailored therapeutics  a) MCS  b) Revascularization in AMI-CS  c) Vasopressors and inotropes in CS  d) Antithrombotics in AMI-CS	Management • Patient selection • Vascular access strategies • MCS tailored to individual CS phenotypes • Optimal strategies for anticoagulation and monitoring (TEG, aPTT, ACT) • Weaning and escalation strategies Impella in AMI-CS • Clinical benefit of LV unloading pre-PCI VA-ECMO in AMI-CS LV venting strategies with VA-ECMO 1) Pharmacologic 2) IABP 3) Impella 4) Atrial septostomy 5) Pulmonary artery cannulation 6) Surgical LV venting Decongestion in cardiorenal syndrome i. Aortix (Procyrion) ii. Reitan Catheter Pump iii. Second Heart Assist • Culprit-vessel vs. multivessel PCI • PCI vs. CABG Safety and efficacy Intravenous P2Y12 inhibition to achieve timely platelet inhibition and to mitigate bleeding risk	• Prospective multicenter registries • RCT • Prospective multicenter registries (NCSI, cVAD) • RCT (DanGer Shock [NCT01633502]) • ECLS-SHOCK (NCT02544594) • ECMO-CS (NCT02301819) • EURO SHOCK (NCT03813134) • ANCHOR (NCT04184635) • Prospective multicenter registries • RCT • Prospective multicenter registries • RCT • RCT • RCT  • Milrinone versus dobutamine in critically ill patients (NCT03207165)  • Norepinephrine vs. Norepinephrine and Dobutamine in Cardiogenic Shock (SHOCK-NORDOB [NCT03340779])  • Efficacy and Safety on Heart Rate Control with Ivabradine in Cardiogenic Shock (ES-FISH [NCT03437369]) • RCT (DAPT-AMI-SHOCK [NCT03551964])
3. Care delivery models  a) Regionalized systems of CS with:   i) Hub-and-spoke networks   ii) Multidisciplinary shock teams  b) Multidisciplinary CICUs with 24/7 staffing	• Improved clinical outcomes • Improved clinical outcomes • Reduced complications • Reduced hospital length of stay • Reduced costs	• Prospective multicenter registries • Prospective multicenter registries
4. Palliative care  a) Early implementation of palliative services in multidisciplinary CS care   1) Shared decision making   2) Goals of care and health values discussions	• Improved patient QOL, well-being • Reduced Complications • Reduced costs	• Prospective multicenter registries • RCT

ACT = activated clotting time; aPTT = activated partial thromboplastin time; cVAD = catheter-based ventricular assist device; DanGer Shock = Danish-German Cardiogenic Shock Trial; DAPT-AMI-SHOCK = Dual Antiplatelet Therapy for Shock Patients with Acute Myocardial Infarction; ECLS-SHOCK = extracorporeal life support in cardiogenic shock; ECMO-CS = •••; LV = left ventricular; MCS = mechanical circulatory support; NCSI = National Cardiogenic Shock Initiative; QOL = quality of life; RCT = randomized controlled trial; SHOCK-NORDOB = Norepinephrine vs Norepinephrine and Dobutamine in Cardiogenic Shock; TEG = thromboelastography; other abbreviations as in Table 2.

HIGHLIGHTS.

• Cardiogenic shock is a hemodynamically complex multisystem syndrome associated with persistently high morbidity and mortality.

• We propose a multidisciplinary approach to diagnosis and management, utilizing standardized protocols that emphasize early invasive hemodynamics and team-based care.

• Development of shock networks with regionalized systems of care may improve clinical outcomes on a large scale.

ABBREVIATIONS AND ACRONYMS

ADHF

acute decompensated heart failure

AMI

acute myocardial infarction

CICU

cardiac intensive care unit

CO

cardiac output

CS

cardiogenic shock

LV

left ventricle/ventricular

MCS

mechanical circulatory support

PAC

pulmonary artery catheter

PCI

percutaneous coronary intervention

RV

right ventricle/ventricular

SCAI

Society for Cardiovascular Angiography and Interventions