Standardized Definitions for Cardiogenic Shock Research and Mechanical Circulatory Support Devices: Scientific Expert Panel From the Shock Academic Research Consortium (SHARC).

The Shock Academic Research Consortium is a multi-stakeholder group, including representatives from the US Food and Drug Administration and other government agencies, industry, and payers, convened to develop pragmatic consensus definitions useful for the evaluation of clinical trials enrolling patients with cardiogenic shock, including trials evaluating mechanical circulatory support devices. Several in-person and virtual meetings were convened between 2020 and 2022 to discuss the need for developing the standardized definitions required for evaluation of mechanical circulatory support devices in clinical trials for cardiogenic shock patients. The expert panel identified key concepts and topics by performing literature reviews, including previous clinical trials, while recognizing current challenges and the need to advance evidence-based practice and statistical analysis to support future clinical trials. For each category, a lead (primary) author was assigned to perform a literature search and draft a proposed definition, which was presented to the subgroup. These definitions were further modified after feedback from the expert panel meetings until a consensus was reached. This manuscript summarizes the expert panel recommendations focused on outcome definitions, including efficacy and safety.

Cardiogenic shock trajectories: is the Society for Cardiovascular Angiography and Interventions definition the right one?

PURPOSE OF REVIEW: We review the current Society for Cardiovascular Angiography and Interventions (SCAI) cardiogenic shock classification system and consider alternatives or iterations that may enhance our current descriptions of cardiogenic shock trajectory. RECENT FINDINGS: Several studies have identified the potential prognostic value of serial SCAI stage re-assessment, usually within the first 24 h of shock onset, to predict deterioration and clinical outcomes across shock causes. In parallel, numerous registry-based analyses support the utility of a more precise assessment of the macrocirculation and microcirculation, leveraging invasive haemodynamics, imaging and additional laboratory and clinical markers. The emergence of machine learning and artificial intelligence capabilities offers the opportunity to integrate multimodal data into high fidelity, real-time metrics to more precisely define trajectory and inform our therapeutic decision making. SUMMARY: Whilst the SCAI staging system remains a pivotal tool in cardiogenic shock assessment, communication and reassessment, it is vital that the sophistication with which we measure and assess shock trajectory evolves in parallel our understanding of the complexity and variability of clinical course and clinical outcomes.

Sex differences in treatments and outcomes of patients with cardiogenic shock: a systematic review and epidemiological meta-analysis.

BACKGROUND: Women are at higher risk of mortality from many acute cardiovascular conditions, but studies have demonstrated differing findings regarding the mortality of cardiogenic shock in women and men. To examine differences in 30-day mortality and mechanical circulatory support use by sex in patients with cardiogenic shock. MAIN BODY: Cochrane Central, PubMed, MEDLINE and EMBASE were searched in April 2024. Studies were included if they were randomised controlled trials or observational studies, included adult patients with cardiogenic shock, and reported at least one of the following outcomes by sex: raw mortality, adjusted mortality (odds ratio) or use of mechanical circulatory support. Out of 4448 studies identified, 81 met inclusion criteria, pooling a total of 656,754 women and 1,018,036 men. In the unadjusted analysis for female sex and combined in-hospital and 30-day mortality, women had higher odds of mortality (Odds Ratio (OR) 1.35, 95% confidence interval (CI) 1.26-1.44, p < 0.001). Pooled unadjusted mortality was 35.9% in men and 40.8% in women (p < 0.001). When only studies reporting adjusted ORs were included, combined in-hospital/30-day mortality remained higher in women (OR 1.10, 95% CI 1.06-1.15, p < 0.001). These effects remained consistent across subgroups of acute myocardial infarction- and heart failure- related cardiogenic shock. Overall, women were less likely to receive mechanical support than men (OR = 0.67, 95% CI 0.57-0.79, p < 0.001); specifically, they were less likely to be treated with intra-aortic balloon pump (OR = 0.79, 95% CI 0.71-0.89, p < 0.001) or extracorporeal membrane oxygenation (OR = 0.84, 95% 0.71-0.99, p = 0.045). No significant difference was seen with use of percutaneous ventricular assist devices (OR = 0.82, 95% CI 0.51-1.33, p = 0.42). CONCLUSION: Even when adjusted for confounders, mortality for cardiogenic shock in women is approximately 10% higher than men. This effect is seen in both acute myocardial infarction and heart failure cardiogenic shock. Women with cardiogenic shock are less likely to be treated with mechanical circulatory support than men. Clinicians should make immediate efforts to ensure the prompt diagnosis and aggressive treatment of cardiogenic shock in women.

The management of heart failure cardiogenic shock: an international RAND appropriateness panel.

BACKGROUND: Observational data suggest that the subset of patients with heart failure related CS (HF-CS) now predominate critical care admissions for CS. There are no dedicated HF-CS randomised control trials completed to date which reliably inform clinical practice or clinical guidelines. We sought to identify aspects of HF-CS care where both consensus and uncertainty may exist to guide clinical practice and future clinical trial design, with a specific focus on HF-CS due to acute decompensated chronic HF. METHODS: A 16-person multi-disciplinary panel comprising of international experts was assembled. A modified RAND/University of California, Los Angeles, appropriateness methodology was used. A survey comprising of 34 statements was completed. Participants anonymously rated the appropriateness of each statement on a scale of 1 to 9 (1-3 as inappropriate, 4-6 as uncertain and as 7-9 appropriate). RESULTS: Of the 34 statements, 20 were rated as appropriate and 14 were rated as inappropriate. Uncertainty existed across all three domains: the initial assessment and management of HF-CS; escalation to temporary Mechanical Circulatory Support (tMCS); and weaning from tMCS in HF-CS. Significant disagreement between experts (deemed present when the disagreement index exceeded 1) was only identified when deliberating the utility of thoracic ultrasound in the immediate management of HF-CS. CONCLUSION: This study has highlighted several areas of practice where large-scale prospective registries and clinical trials in the HF-CS population are urgently needed to reliably inform clinical practice and the synthesis of future societal HF-CS guidelines.

Extending the 'host response' paradigm from sepsis to cardiogenic shock: evidence, limitations and opportunities.

Recent clinical and research efforts in cardiogenic shock (CS) have largely focussed on the restoration of the low cardiac output state that is the conditio sine qua non of the clinical syndrome. This approach has failed to translate into improved outcomes, and mortality has remained static at 30-50%. There is an unmet need to better delineate the pathobiology of CS to understand the observed heterogeneity of presentation and treatment effect and to identify novel therapeutic targets. Despite data in other critical illness syndromes, specifically sepsis, the role of dysregulated inflammation and immunity is hitherto poorly described in CS. High-dimensional molecular profiling, particularly through leukocyte transcriptomics, may afford opportunity to better characterise subgroups of patients with shared mechanisms of immune dysregulation. In this state-of-the-art review, we outline the rationale for considering molecular subtypes of CS. We describe how high-dimensional molecular technologies can be used to identify these subtypes, and whether they share biological features with sepsis and other critical illness states. Finally, we propose how the identification of molecular subtypes of patients may enrich future clinical trial design and identification of novel therapies for CS.

RAND appropriateness panel to determine the applicability of UK guidelines on the management of acute respiratory distress syndrome (ARDS) and other strategies in the context of the COVID-19 pandemic.

BACKGROUND: COVID-19 has become the most common cause of acute respiratory distress syndrome (ARDS) worldwide. Features of the pathophysiology and clinical presentation partially distinguish it from 'classical' ARDS. A Research and Development (RAND) analysis gauged the opinion of an expert panel about the management of ARDS with and without COVID-19 as the precipitating cause, using recent UK guidelines as a template. METHODS: An 11-person panel comprising intensive care practitioners rated the appropriateness of ARDS management options at different times during hospital admission, in the presence or absence of, or varying severity of SARS-CoV-2 infection on a scale of 1-9 (where 1-3 is inappropriate, 4-6 is uncertain and 7-9 is appropriate). A summary of the anonymised results was discussed at an online meeting moderated by an expert in RAND methodology. The modified online survey comprising 76 questions, subdivided into investigations (16), non-invasive respiratory support (18), basic intensive care unit management of ARDS (20), management of refractory hypoxaemia (8), pharmacotherapy (7) and anticoagulation (7), was completed again. RESULTS: Disagreement between experts was significant only when addressing the appropriateness of diagnostic bronchoscopy in patients with confirmed or suspected COVID-19. Adherence to existing published guidelines for the management of ARDS for relevant evidence-based interventions was recommended. Responses of the experts to the final survey suggested that the supportive management of ARDS should be the same, regardless of a COVID-19 diagnosis. For patients with ARDS with COVID-19, the panel recommended routine treatment with corticosteroids and a lower threshold for full anticoagulation based on a high index of suspicion for venous thromboembolic disease. CONCLUSION: The expert panel found no reason to deviate from the evidence-based supportive strategies for managing ARDS outlined in recent guidelines.

The Intersection Between Heart Failure and Critical Care Cardiology: An International Perspective on Structure, Staffing, and Design Considerations.

The overall patient population in contemporary cardiac intensive care units (CICUs) has only increased with respect to patient acuity, complexity, and illness severity. The current population has more cardiac and noncardiac comorbidities, a higher prevalence of multiorgan injury, and consumes more critical care resources than previously. Patients with heart failure (HF) now occupy a large portion of contemporary tertiary or quaternary care CICU beds around the world. In this review, we discuss the core issues that relate to the care of critically ill patients with HF, including global perspectives on the organization, designation, and collaboration of CICUs regionally and across institutions, as well as unique models for provisioning care for patients with HF within a health care setting. The latter includes a discussion of traditional and emerging models, specialized HF units, the makeup and implementation of multidisciplinary team-based decision-making, and cardiac critical care admission and triage practices. This article illustrates the ways in which critically ill patients with HF have helped to shape contemporary CICUs throughout the world and explores how these very patients will similarly help to inform the future maturation of these specialized critical care units. Finally, we will critically examine broad, contemporary, international models of HF and cardiac critical care delivery in North America, Europe, South America, and Asia, and conclude with opportunities for the further investigation and generation of evidence for care delivery.

Early quantitative infrared pupillometry for prediction of neurological outcome in patients admitted to intensive care after out-of-hospital cardiac arrest.

BACKGROUND: Quantitative pupillometry is recommended for neuroprognostication after out-of-hospital cardiac arrest 72 h or more after ICU admission, but the feasibility and utility of earlier assessment is unknown. METHODS: This was a study of the utility of an early quantitative pupillometry index in predicting neurological outcome in patients with reduced consciousness after out-of-hospital cardiac arrest. Quantitative infrared pupillometry index was measured at 0, 6, 24, 48, and 72 h from admission. Acceptable predictive utility was defined as a positive predictive value of >95% and false positive rate of zero, with a narrow 95% confidence interval (95% CI). RESULTS: At least one quantitative pupillometry index measurement was available from within the first 6 h for all 77 patients who met inclusion criteria. A quantitative pupillometry index ≤2.4 at baseline and ≤2.3 within the first 6 h met the criteria for utility. The positive predictive value of the baseline cut-off (≤2.4) for poor neurological outcome was 1.00 (95% CI, 0.54-1.00) with an estimated false positive rate of 0% (95% CI, 0-9%). The positive predictive value of the 6 h cut-off (≤2.3) for poor neurological outcome was 1.00 (95% CI, 0.59-1.00) with an estimated false positive rate of 0% (95% CI, 0-8%). Sensitivities of these cut-offs for ruling out poor neurological outcomes at 0 and 6 h were 19% and 22%, respectively. Of seven patients with a quantitative pupillometry index ≤2.3 within 6 h of ICU admission, none survived. Analyses that used quantitative pupillometry index measurements from 24 to 72 h, but excluded baseline and 6 h values, were not predictive by the utility criteria. CONCLUSIONS: Quantitative pupillometry within 6 h of ICU admission after out-of-hospital cardiac arrest may identify patients with a very low chance of neurologically intact survival. Further studies of early quantitative pupillometry in this population are warranted.

Cardiogenic Shock After Acute Myocardial Infarction: A Review.

IMPORTANCE: Cardiogenic shock affects between 40 000 and 50 000 people in the US per year and is the leading cause of in-hospital mortality following acute myocardial infarction. OBSERVATIONS: Thirty-day mortality for patients with cardiogenic shock due to myocardial infarction is approximately 40%, and 1-year mortality approaches 50%. Immediate revascularization of the infarct-related coronary artery remains the only treatment for cardiogenic shock associated with acute myocardial infarction supported by randomized clinical trials. The Percutaneous Coronary Intervention Strategies with Acute Myocardial Infarction and Cardiogenic Shock (CULPRIT-SHOCK) clinical trial demonstrated a reduction in the primary outcome of 30-day death or kidney replacement therapy; 158 of 344 patients (45.9%) in the culprit lesion revascularization-only group compared with 189 of 341 patients (55.4%) in the multivessel percutaneous coronary intervention group (relative risk, 0.83 [95% CI, 0.71-0.96]; P = .01). Despite a lack of randomized trials demonstrating benefit, percutaneous mechanical circulatory support devices are frequently used to manage cardiogenic shock following acute myocardial infarction. CONCLUSIONS AND RELEVANCE: Cardiogenic shock occurs in up to 10% of patients immediately following acute myocardial infarction and is associated with mortality rates of nearly 40% at 30 days and 50% at 1 year. Current evidence and clinical practice guidelines support immediate revascularization of the infarct-related coronary artery as the primary therapy for cardiogenic shock following acute myocardial infarction.

Novel anti-tumour necrosis factor receptor-1 (TNFR1) domain antibody prevents pulmonary inflammation in experimental acute lung injury.

BACKGROUND: Tumour necrosis factor alpha (TNF-α) is a pleiotropic cytokine with both injurious and protective functions, which are thought to diverge at the level of its two cell surface receptors, TNFR1 and TNFR2. In the setting of acute injury, selective inhibition of TNFR1 is predicted to attenuate the cell death and inflammation associated with TNF-α, while sparing or potentiating the protective effects of TNFR2 signalling. We developed a potent and selective antagonist of TNFR1 (GSK1995057) using a novel domain antibody (dAb) therapeutic and assessed its efficacy in vitro, in vivo and in a clinical trial involving healthy human subjects. METHODS: We investigated the in vitro effects of GSK1995057 on human pulmonary microvascular endothelial cells (HMVEC-L) and then assessed the effects of pretreatment with nebulised GSK1995057 in a non-human primate model of acute lung injury. We then tested translation to humans by investigating the effects of a single nebulised dose of GSK1995057 in healthy humans (n=37) in a randomised controlled clinical trial in which subjects were subsequently exposed to inhaled endotoxin. RESULTS: Selective inhibition of TNFR1 signalling potently inhibited cytokine and neutrophil adhesion molecule expression in activated HMVEC-L monolayers in vitro (P<0.01 and P<0.001, respectively), and also significantly attenuated inflammation and signs of lung injury in non-human primates (P<0.01 in all cases). In a randomised, placebo-controlled trial of nebulised GSK1995057 in 37 healthy humans challenged with a low dose of inhaled endotoxin, treatment with GSK1995057 attenuated pulmonary neutrophilia, inflammatory cytokine release (P<0.01 in all cases) and signs of endothelial injury (P<0.05) in bronchoalveolar lavage and serum samples. CONCLUSION: These data support the potential for pulmonary delivery of a selective TNFR1 dAb as a novel therapeutic approach for the prevention of acute respiratory distress syndrome. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01587807.

The pulmonary endothelium in acute respiratory distress syndrome: insights and therapeutic opportunities.

The pulmonary endothelium is a dynamic, metabolically active layer of squamous endothelial cells ideally placed to mediate key processes involved in lung homoeostasis. Many of these are disrupted in acute respiratory distress syndrome (ARDS), a syndrome with appreciable mortality and no effective pharmacotherapy. In this review, we consider the role of the pulmonary endothelium as a key modulator and orchestrator of ARDS, highlighting advances in our understanding of endothelial pathobiology and their implications for the development of endothelial-targeted therapeutics including cell-based therapies. We also discuss mechanisms to facilitate the translation of preclinical data into effective therapies including the application of biomarkers to phenotype patients with ARDS with a predominance of endothelial injury and emerging biotechnologies that could enhance delivery, discovery and testing of lung endothelial-specific therapeutics.

Extra-cardiac management of cardiogenic shock in the intensive care unit.

Cardiogenic shock (CS) is a heterogeneous clinical syndrome characterized by low cardiac output leading to end-organ hypoperfusion. Organ dysoxia ranging from transient organ injury to irreversible organ failure and death occurs across all CS etiologies but differing by incidence and type. Herein, we review the recognition and management of respiratory, renal and hepatic failure complicating CS. We also discuss unmet needs in the CS care pathway and future research priorities for generating evidence-based best practices for the management of extra-cardiac sequelae. The complexity of CS admitted to the contemporary cardiac intensive care unit demands a workforce skilled to care for these extra-cardiac critical illness complications with an appreciation for how cardio-systemic interactions influence critical illness outcomes in afflicted patients.

Heart failure related cardiogenic shock: An ISHLT consensus conference content summary.

In recent years, there have been significant advancements in the understanding, risk-stratification, and treatment of cardiogenic shock (CS). Despite improved pharmacologic and device-based therapies for CS, short-term mortality remains as high as 50%. Most recent efforts in research have focused on CS related to acute myocardial infarction, even though heart failure related CS (HF-CS) accounts for >50% of CS cases. There is a paucity of high-quality evidence to support standardized clinical practices in approach to HF-CS. In addition, there is an unmet need to identify disease-specific diagnostic and risk-stratification strategies upon admission, which might ultimately guide the choice of therapies, and thereby improve outcomes and optimize resource allocation. The heterogeneity in defining CS, patient phenotypes, treatment goals and therapies has resulted in difficulty comparing published reports and standardized treatment algorithms. An International Society for Heart and Lung Transplantation (ISHLT) consensus conference was organized to better define, diagnose, and manage HF-CS. There were 54 participants (advanced heart failure and interventional cardiologists, cardiothoracic surgeons, critical care cardiologists, intensivists, pharmacists, and allied health professionals), with vast clinical and published experience in CS, representing 42 centers worldwide. State-of-the-art HF-CS presentations occurred with subsequent breakout sessions planned in an attempt to reach consensus on various issues, including but not limited to models of CS care delivery, patient presentations in HF-CS, and strategies in HF-CS management. This consensus report summarizes the contemporary literature review on HF-CS presented in the first half of the conference (part 1), while the accompanying document (part 2) covers the breakout sessions where the previously agreed upon clinical issues were discussed with an aim to get to a consensus.

Consensus statements from the International Society for Heart and Lung Transplantation consensus conference: Heart failure-related cardiogenic shock.

The last decade has brought tremendous interest in the problem of cardiogenic shock. However, the mortality rate of this syndrome approaches 50%, and other than prompt myocardial revascularization, there have been no treatments proven to improve the survival of these patients. The bulk of studies have been in patients with acute myocardial infarction, and there is little evidence to guide the clinician in those patients with heart failure cardiogenic shock (HF-CS). An International Society for Heart and Lung Transplant consensus conference was organized to better define, diagnose, and manage HF-CS. There were 54 participants (advanced heart failure and interventional cardiologists, cardiothoracic surgeons, critical care cardiologists, intensivists, pharmacists, and allied health professionals) with vast clinical and published experience in CS, representing 42 centers worldwide. This consensus report summarizes the results of a premeeting survey answered by participants and the breakout sessions where predefined clinical issues were discussed to achieve consensus in the absence of robust data. Key issues discussed include systems for CS management, including the "hub-and-spoke" model vs a tier-based network, minimum levels of data to communicate when considering transfer, disciplines that should be involved in a "shock team," goals for mechanical circulatory support device selection, and optimal flow on such devices. Overall, the document provides expert consensus on some important issues facing practitioners managing HF-CS. It is hoped that this will clarify areas where consensus has been reached and stimulate future research and registries to provide insight regarding other crucial knowledge gaps.

EPidemiology Of Cardiogenic sHock in Scotland (EPOCHS): A multicentre, prospective observational study of the prevalence, management and outcomes of cardiogenic shock in Scotland.

Background: Despite high rates of cardiovascular disease in Scotland, the prevalence and outcomes of patients with cardiogenic shock are unknown. Methods: We undertook a prospective observational cohort study of consecutive patients with cardiogenic shock admitted to the intensive care unit (ICU) or coronary care unit at 13 hospitals in Scotland for a 6-month period. Denominator data from the Scottish Intensive Care Society Audit Group were used to estimate ICU prevalence; data for coronary care units were unavailable. We undertook multivariable logistic regression to identify factors associated with in-hospital mortality. Results: In total, 247 patients with cardiogenic shock were included. After exclusion of coronary care unit admissions, this comprised 3.0% of all ICU admissions during the study period (95% confidence interval [CI] 2.6%-3.5%). Aetiology was acute myocardial infarction (AMI) in 48%. The commonest vasoactive treatment was noradrenaline (56%) followed by adrenaline (46%) and dobutamine (40%). Mechanical circulatory support was used in 30%. Overall in-hospital mortality was 55%. After multivariable logistic regression, age (odds ratio [OR] 1.04, 95% CI 1.02-1.06), admission lactate (OR 1.10, 95% CI 1.05-1.19), Society for Cardiovascular Angiographic Intervention stage D or E at presentation (OR 2.16, 95% CI 1.10-4.29) and use of adrenaline (OR 2.73, 95% CI 1.40-5.40) were associated with mortality. Conclusions: In Scotland the prevalence of cardiogenic shock was 3% of all ICU admissions; more than half died prior to discharge. There was significant variation in treatment approaches, particularly with respect to vasoactive support strategy.

Clinical presentation, shock severity and mortality in patients with de novo versus acute-on-chronic heart failure-related cardiogenic shock.

AIMS: Heart failure-related cardiogenic shock (HF-CS) accounts for a significant proportion of CS cases. Whether patients with de novo HF and those with acute-on-chronic HF in CS differ in clinical characteristics and outcome remains unclear. The aim of this study was to evaluate differences in clinical presentation and mortality between patients with de novo and acute-on-chronic HF-CS. METHODS AND RESULTS: In this international observational study, patients with HF-CS from 16 tertiary care centres in five countries were enrolled between 2010 and 2021. To investigate differences in clinical presentation and 30-day mortality, adjusted logistic/Cox regression models were fitted. Patients (n = 1030) with HF-CS were analysed, of whom 486 (47.2%) presented with de novo HF-CS and 544 (52.8%) with acute-on-chronic HF-CS. Traditional markers of CS severity (e.g. blood pressure, heart rate and lactate) as well as use of treatments were comparable between groups. However, patients with acute-on-chronic HF-CS were more likely to have a higher CS severity and also a higher mortality risk, after adjusting for relevant confounders (de novo HF 45.5%, acute-on-chronic HF 55.9%, adjusted hazard ratio 1.38, 95% confidence interval 1.10-1.72, p = 0.005). CONCLUSION: In this large HF-CS cohort, acute-on-chronic HF-CS was associated with more severe CS and higher mortality risk compared to de novo HF-CS, although traditional markers of CS severity and use of treatments were comparable. These findings highlight the vast heterogeneity of patients with HF-CS, emphasize that HF chronicity is a relevant disease modifier in CS, and indicate that future clinical trials should account for this.