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.

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.

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.

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.

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.

Time for a rethink in cardiogenic shock: the shock to survival framework document.

Cardiogenic shock remains a time-critical, complex syndrome that continues to present challenges to clinicians and healthcare systems. Despite advances in the fields of cardiovascular and critical care medicine, mortality remains high. This article summarises the recent shock to survival document, which outlined the current and ideal future state of cardiogenic shock care nationally to improve patient outcomes. Shock to survival emphasises the need for education and training in the early recognition of the hypoperfusion that is pathognomomic of cardiogenic shock. Improved provision of focused cardiac ultrasound is essential to confirm a cardiac cause. Early identification of the patient with cardiogenic shock should be supported by access to defined pathways of care, including specialist shock centres and multiprofessional teams with domain expertise and the capability to manage the myriad of causative aetiologies. Given the absence of high-quality data to inform practice nationally, robust datasets are an unmet need to inform best practice, guide design of clinical services and pathways and drive innovation through research and clinical trials.

Biomarkers of acute lung injury: worth their salt?

The validation of biomarkers has become a key goal of translational biomedical research. The purpose of this article is to discuss the role of biomarkers in the management of acute lung injury (ALI) and related research. Biomarkers should be sensitive and specific indicators of clinically important processes and should change in a relevant timeframe to affect recruitment to trials or clinical management. We do not believe that they necessarily need to reflect pathogenic processes. We critically examined current strategies used to identify biomarkers and which, owing to expedience, have been dominated by reanalysis of blood derived markers from large multicenter Phase 3 studies. Combining new and existing validated biomarkers with physiological and other data may add predictive power and facilitate the development of important aids to research and therapy.

Translational research: what does it mean, what has it delivered and what might it deliver?

PURPOSE OF REVIEW: In this article, we review recent developments in translational research in the fields of acute lung injury, acute kidney injury and sepsis with a focus on emerging biomarkers and outline future advances in the field. RECENT FINDINGS: There is currently a significant and unmet need for high quality translational research in critical care. The emergence of '-omics' technologies and sophisticated imaging techniques have resulted in a rapid growth of emerging biomarkers. Biomarkers would ideally provide early and reliable endpoints for proof of concept in clinical trials and inform clinical decision making through earlier and more precise diagnosis and risk stratification. SUMMARY: Despite significant investment in basic science and time-consuming clinical trials, the majority of pharmacological interventions developed for critical illness have yet to translate into measurable clinical benefit. Future validation and qualification of emerging biomarkers allied to advances in pharmacogenomic profiling have the potential to provide valuable clinical information while accurately phenotyping patients enrolled in future clinical trials.

Clinician Perceptions of the Impact of a Shock Team Approach in the Management of Cardiogenic Shock: A Qualitative Study.

INTRODUCTION: Designated cross-specialty shock teams have been proposed as a mechanism to manage the complexity of decision-making and facilitate collaborative, patient-centred care-planning in cardiogenic shock. Observational data support the notion that shock protocols and teams may improve survival, but there is an absence of data interrogating how clinicians engage with and value the shock team paradigm. This study sought to explore clinician perceptions of the value of the shock call system on decision making and the management of CGS. MATERIALS & METHODS: A descriptive qualitative approach was used. A focus group, semi-structured interview was conducted with twelve cross-specialty members of a shock team at a single tertiary cardiac centre in the UK. The focus group was audio-recorded, transcribed, and thematically analysed to capture and describe the clinicians' experience and perceptions of shock team discussions. RESULTS: Eight cardiac intensivists, two heart failure cardiologists, one cardiothoracic surgeon and one interventional cardiologist participated in the focus group. Four key themes were identified from the discussions: supportive decision making; team communication; governance and learning; and future directions. CONCLUSION: This study supports the notion that cross-specialty, real-time patient discussion may provide added value beyond protocolised decision making and account for the complexities of managing patients in a field where definitive, high-quality evidence to guide practice is currently limited.

Contemporary Management of Cardiogenic Shock: A RAND Appropriateness Panel Approach.

BACKGROUND: Current practice in cardiogenic shock is guided by expert opinion in guidelines and scientific statements from professional societies with limited high quality randomized trial data to inform optimal patient management. An international panel conducted a modified Delphi process with the intent of identifying aspects of cardiogenic shock care where there was uncertainty regarding optimal patient management. METHODS: An 18-person multidisciplinary panel comprising international experts was convened. A modified RAND/University of California Los Angeles appropriateness methodology was used. A survey comprising 70 statements was completed. Participants anonymously rated the appropriateness of each statement on a scale of 1 to 9: 1 to 3 inappropriate, 4 to 6 uncertain, and 7 to 9 appropriate. A summary of the results was discussed as a group, and the survey was iterated and completed again before final analysis. RESULTS: There was broad alignment with current international guidelines and consensus statements. Overall, 44 statements were rated as appropriate, 19 as uncertain, and 7 as inappropriate. There was no disagreement with a disagreement index <1 for all statements. Routine fluid administration was deemed to be inappropriate. Areas of uncertainty focused panel on pre-PCI interventions, the use of right heart catheterization to guide management, routine use of left ventricular unloading strategies, and markers of futility when considering escalation to mechanical circulatory support. CONCLUSIONS: While there was broad alignment with current guidance, an expert panel found several aspects of care where there was clinical equipoise, further highlighting the need for randomized controlled trials to better guide patient management and decision making in cardiogenic shock.

Extra-corporeal membrane oxygenation and Eculizumab: Atypical treatments for typical haemolytic uraemic syndrome.

A 19-year-old female with no medical history presented with bloody diarrhoea. Investigations revealed an acute kidney injury, thrombocytopenia and microangiopathic haemolysis. A diagnosis of haemolytic uraemic syndrome secondary to Shiga toxin-producing Escherichia coli 055 was confirmed and supportive therapy commenced in the intensive therapy unit. On day 11 of her admission, she rapidly deteriorated with evidence of refractory cardiogenic shock and neurological involvement, both features associated with a poor prognosis. Cross-specialty collaboration prompted a trial of veno-arterial extra-corporeal membrane oxygenation and Eculizumab, a complement inhibitor normally reserved for atypical haemolytic uraemic syndrome, as a bridge to organ recovery. To our knowledge, herein we present the first adult patient with haemolytic uraemic syndrome induced cardiogenic shock successfully supported to cardiac recovery with extra-corporeal membrane oxygenation. The potential role for Eculizumab in Shiga toxin-producing Escherichia coli/typical haemolytic uraemic syndrome is also discussed.

Sub30: Protocol for the Sub30 feasibility study of a pre-hospital Extracorporeal membrane oxygenation (ECMO) capable advanced resuscitation team at achieving blood flow within 30 ​min in patients with refractory out-of-hospital cardiac arrest.

BACKGROUND: Out-of-hospital cardiac arrest carries a poor prognosis with survival less than 10% in many patient cohorts. Survival is inversely associated with duration of resuscitation as external chest compressions do not provide sufficient blood flow to prevent irreversible organ damage during a prolonged resuscitation. Extracorporeal membrane oxygenation (ECMO) instituted during cardiac arrest can provide normal physiological blood flows and is termed Extracorporeal Cardio-Pulmonary Resuscitation (ECPR). ECPR may improve survival when used with in-hospital cardiac arrests. This possible survival benefit has not been replicated in trials of out-of-hospital cardiac arrests, possibly because of the additional time it takes to transport the patient to hospital and initiate ECPR. Pre-hospital ECPR may shorten the time between cardiac arrest and physiological blood flows, potentially improving survival. It may also mitigate some of the neurological injury that many survivors suffer. METHODS: Sub30 is a prospective six patient feasibility study. The primary aim is to test whether it is possible to institute ECPR within 30 ​min of collapse in adult patients with refractory out of hospital cardiac arrest (OHCA). The secondary aims are to gather preliminary data on clinical outcomes, resource utilisation, and health economics associated with rapid ECPR delivery in order to plan any subsequent clinical investigation or clinical service. On study days a dedicated fast-response vehicle with ECPR capability will be tasked to out-of-hospital cardiac arrests in an area of London served by Barts Heart Centre. If patients suffer a cardiac arrest refractory to standard advanced resuscitation and meet eligibility criteria, ECPR will be started in the pre-hospital environment. DISCUSSION: Delivering pre-hospital ECPR within 30 ​min of an out-of-hospital cardiac arrest presents significant ethical, clinical, governance and logistical challenges. Prior to conducting an efficacy study of ECPR the feasibility of timely and safe application must be demonstrated first. Extensive planning, multiple high-fidelity multiagency simulations and a unique collaboration between pre-hospital and in-hospital institutions will allow us to test the feasibility of this intervention in London. The study has been reviewed, refined and endorsed by the International ECMO Network (ECMONet). TRIAL REGISTRATION: Clinicaltrials. gov NCT03700125, prospectively registered October 9, 2018.