How Should We Develop New Risk Scores for Cardiogenic Shock?

Cardiogenic shock (CS) is associated with a high mortality rate, and prognostic improvement is problematic for various reasons, including the diversity of causes, heterogeneous clinical course, miscellaneous therapeutic options, and the flood of novel emerging therapies.¹ Many risk scores for CS have been developed to achieve early recognition of shock (i.e., definition of shock), appropriate decision on treatment strategy, and estimation of patient prognosis. Kalra et al reviewed the CS scores by dividing them into 3 categories: (1) those focused on critically ill patients requiring intensive care; (2) those focused on patients with acute myocardial infarction (AMI) and CS; and (3) those pertinent to patients with CS who are being sustained by mechanical support devices.² The fact that most CS scores are cumbersome and focus on a specific clinical course of CS limits their clinical usage. Several classifications and landmark clinical trials that contribute to the recognition of CS are referenced to the Japanese Circulation Society (JCS) guidelines for the management of patients with CS (Table 1).^3–8 Meanwhile, the absolute value of CS scores developed from a specific CS registry is not clearly recommended in the Guidelines for diagnosis and treatment of acute and chronic heart failure⁹ and Guidelines on diagnosis and treatment of acute coronary syndrome.¹⁰ The Society of Cardiovascular Angiography and Interventions (SCAI) recently proposed a clinical expert consensus statement on the classification of CS, as a staging schema for CS based on examination findings, laboratory markers, and hemodynamics.¹¹

Table 1. Classification and Landmark Clinical Trials Related to the Definition of CS in JCS Guideline

Score / trial	Variables	Conclusion
Definition of CS
Killip classification 　Killip et al.3 Am J Cardiol 1967 　PMID: 6059183	Systolic BP Heart (S3) and lung (rales) sound Physical examination	Patients with systolic BP ≤90 mmHg, cyanosis, and cold clammy skin are classified as class IV, which indicates high mortality rate
Forrester subset 　Forrester, et al.4 　Am J Cardiol 1977 　PMID: 835473	CI PCWP	Patients with CI ≤2.2 and PCWP ≥18 mmHg are classified as subset IV, which indicates high mortality rate
SHOCK 　Hochman, et al.5 　Am Heart J 1999 　PMID: 9924166	Systolic BP Urine output CI PCWP Physical examination	Patients with clinical (systolic BP <90 mmHg for ≥30 min / systolic BP ≥90 mmHg with support/evidence of hypoperfusion: urine output <30 mL/h, cold extremities) or hemodynamic (CI <2.2 L/min/m2 / PCWP >15 mmHg) criteria are enrolled as CS In patients with AMI associated with CS, early revascularization significantly better than medical therapy in terms of survival at 6 months
Nohria-Stevenson classification 　Nohria, et al.6 　J Am Coll Cardiol 2003 　PMID: 12767667	Signs of congestion: Orthopnea/ jugular venous distention/edema/ ascites/hepatojugular reflex Signs of hypoperfusion: Low pulse pressure/pulseless alternans/ symptomatic/hypotension (without orthostasis)/cool extremities/ impaired mentation	Patients with evidence of both congestion and hypoperfusion are classified as subset C (wet-cold, CS), which indicates high mortality rate
Levy, et al.7 　Crit Care Med 2011 　PMID: 21037469	Systolic or mean BP CI PCWP Urine output Lactate level	Patients who present (1) acute or chronic heart failure with an ejection fraction of 30% and CI <2.2 L/min/m2, (2) absence of hypovolemia; (3) systolic BP <90 mmHg or mean BP <60 mmHg, or a drop in mean BP of 30 mmHg despite dopamine; (4) urine output <0.5 mL/kg/h resistant to diuretics; (5) lactate level of 2 mmol/L; and (6) signs of hypoperfusion are defined as CS The study was designed to compare the effects of epinephrine and norepinephrine-dobutamine in dopamine-resistant non-ischemic CS
Culprit-SHOCK 　Thiele, et al.8 　Eur Heart J 2017 　PMID: 29020341	Systolic BP Pulmonary congestion Urine output Arterial lactate level Physical examination	Patients with systolic BP ≤90 mmHg for >30 min or the use of catecholamine to maintain systolic BP >90 mmHg, clinical signs of pulmonary congestion, and impaired organ perfusion with ≥1 of the following manifestations: altered mental status, cold and clammy skin and limbs, urine output ≤30 mL/h, or an arterial lactate level ≥2.0 mmol/L are enrolled as CS In the primary PCI of patients with AMI associated with multivessel disease who developed CS, PCI of the responsible lesion alone was associated with a lower risk of the composite endpoint of death and severe renal failure requiring renal replacement therapy at 30 days than was PCI of the multivessel lesion

AMI, acute myocardial infarction; BP, blood pressure; CI, cardiac index; CS, cardiogenic shock; JCS, Japanese Circulation Society; PCI, percutaneous coronary intervention; PCWP, pulmonary wedge pressure.

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In this issue of the Journal, Hyun et al¹² propose a novel CS score to optimize the timing of the initiation of veno-arterial extracorporeal membrane oxygenation (VA-ECMO). It is well known that VA-ECMO initiation before the development of organ dysfunction leads to favorable outcomes.¹³ In addition, an increase in the amount of vasoactive or inotropic agents aggravates end-organ perfusion, multiorgan dysfunction, and worsening clinical outcomes.¹⁴ Therefore, patients with refractory CS treated with VA-ECMO have a complicated and heterogeneous condition caused by various underlying etiologies and exacerbated by a significant end-organ supply-demand mismatch, leading to a high rate of in-hospital death despite the administration of vasoactive medications.¹⁵ As shown in Table 2, several CS scores focusing on the management of mechanical circulatory support such as intra-aortic balloon pumping (IABP),¹⁶ Impella,^17,18 left ventricular assist device (LVAD),¹⁹ and VA-ECMO^20,21 have been proposed and are referenced in the JCS guidelines.^9,10 Hyun et al demonstrated that a high (≥32) vasoactive-inotropic score (VIS) before the initiation of VA-ECMO was associated with the risk of in-hospital death. They concluded that VIS may be a potential clinical marker for determining the timing of VA-ECMO, as well as predicting in-hospital outcomes of pediatric patients undergoing cardiac surgery, adult patients with CS, and adult patients with post-cardiotomy shock with VA-ECMO support. We need to examine whether the absolute value of VIS 32 derived from a limited cohort varies by region, healthcare system, and patient background. The authors have also addressed the point that the potential benefit of initiating VA-ECMO before reaching higher VIS was prominent in patients with CS of non-ischemic origin. Differences in clinical presentation, the nature and reversibility of underlying cardiovascular diseases, and the clinical situation at the time of VA-ECMO initiation may affect the difference in the VIS benefit for VA-ECMO initiation. Considering these limitations, this study demonstrates that there is no “One size fits all” score of CS. Thus, further studies to investigate the practical use of VIS combined with other CS scores are required to establish adequate risk stratification and management of CS with ECMO support.

Table 2. Classification and Landmark Clinical Trials Related to the Indication for Mechanical Circulatory Support in JCS Guideline

Score / trial	Variables	Conclusion
Indication for mechanical circulatory support
Oshima, et al.20 　Int Heart J 2006 　PMID: 16960412	APACHE II score Vital signs: HR/mean BP/respiratory rate/ temperature Glasgow Coma Score Venous blood tests: hematocrit/white blood cell count/serum potassium/serum sodium/serum creatinine Arterial blood gas tests: serum pH/PaO2	The limitation of PCPS therapy for patients with an episode of cardiac arrest who did not show improvement in their APACHE II score, urine output, serum lactate levels, and catecholamine dose received within 72 h after PCPS induction
ISAR-SHOCK 　Seyfarth, et al.17 　J Am Coll Cardiol 2008 　PMID: 19007597	The same as SHOCK trial (Hochman et al.5 1999)	In patients presenting with CS caused by AMI, the use of Impella LP or 2.5 is feasible and safe and provides superior hemodynamic support compared with standard treatment using an IABP
INTERMACS/J-MACS classification 　Stevenson, et al.19 　J Heart Lung Transplant 2009 　PMID: 19481012	BP Signs of hypoperfusion PH Lactate level	Patients with critical CS (Crash and burn) are defined as profile 1 and recommended definitive intervention within hours
IABP-SHOCKII 　Thiele, et al.16 　N Engl J Med 2012 　PMID: 22920912	The same as the Culprit-SHOCK trial (Thiele, et al.8 2017)	In patients undergoing early revascularization for AMI complicated by CS, the addition of IABP to optimal medical therapy did not significantly reduce mortality rate at 30 days
Survival After Veno-arterial ECMO 　(SAVE) score 　Schmidt, et al.21 　Eur Heart J 2015 　PMID: 26033984	SAVE score Diagnosis Age Weight Acute pre-ECMO organ failure Chronic renal failure Duration of intubation prior to initiation of ECMO Peak inspiratory pressure Pre-ECMO cardiac arrest Diastolic BP before ECMO Pulse pressure before ECMO HCO3 before ECMO	The SAVE score may be a tool to predict survival of patients receiving ECMO for refractory CS
IMPRESS-SHOCK 　Ouweneel, et al.18 　J Am Coll Cardiol 2017 　PMID: 27810347	Systolic BP	Severe CS defined as systolic BP <90 mmHg for >30 min or the need for inotropes or vasopressors to maintain systolic BP >90 mmHg In patients with severe CS after AMI, routine treatment with pMCS was not associated with reduced 30-day mortality rate compared with IABP

APACHE, Acute Physiology and Chronic Health Evaluation; HR, heart rate; ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon pump; LVAD, left ventricular assist device; PCPS, percutaneous cardiopulmonary support; pMCS, percutaneous mechanical circulatory support; SAVE, Survival After Veno-Arterial ECMO. Other abbreviations as in Table 1.

How should we develop a new CS score? The ideal risk prediction model is one that can be used dynamically in multiple scenarios with universally available metrics. However, appropriate CS scores may differ among patients with CS, and the patients may recover with conservative pharmacological treatment, require advanced treatment to survive, or may die despite receiving treatment.² Thus, situation-specific development in CS scores, as shown in this study,¹² may be one option. To utilize such CS scores, it is also necessary to construct a shock protocol that integrates multiple CS scores. Mebazaa et al proposed multidisciplinary practical guidance for CS management using parameters adopted from routine emergency medical care.²² A study of the Detroit Cardiogenic Shock Initiative demonstrated that medical centers that adopted a regional shock protocol emphasizing the delivery of early mechanical circulatory support (MCS) with invasive hemodynamic monitoring and CS scores can achieve rapid door-to-support times and can improve clinical outcomes in patients who present with AMI and CS.²³ In addition to the classical variables for estimating the risk of CS, such as the patient’s characteristics, and hemodynamic and biochemical factors, we should consider social and hospital factors such as the cost-benefit of device therapy, available treatment options, and the capabilities of medical staff in the hospital or area.²⁴ Recently, CS scores have been proposed using the techniques of omics research,²⁵ and artificial intelligence.²⁶ Because it is well known that physiological indices are insufficient for estimating long-term outcomes of acute cardiovascular diseases, the development of new CS scores using bioinformatic approaches is also expected.

Optimization of CS management is the biggest challenge in the field of cardiovascular diseases. In addition to accumulating evidence of CS scores within a limited cohort of CS, further studies are required to establish an ideal protocol for CS treatment using multiple CS scores and validation using high-quality CS registries across countries and regions.

Funding / Support / Conflict of Interest Disclosures

None.

IRB Information

Not applicable.

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