EndotyPIng PreHospitAl de Novo Acute hYpoxemic Respiratory Failure

Study Overview
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Brief Summary
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We attempt to perform dynamic endotyping of critically ill patients presenting in the emergency department with de novo acute hypoxemic respiratory failure (AHRF). We also attempt to identify what clinical, radiological, physiological and biological variables collected early in the course of AHRF correlate with subsequent mortality and/or persistent severe hypoxemia.

Detailed Description
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Rationale: Even before the pandemic of the new coronavirus disease (COVID-19), acute respiratory distress syndrome (ARDS), the most severe form of acute hypoxemic respiratory failure (AHRF), constituted a public health challenge. Despite the intense research on identifying targeted pharmacological therapies for ARDS, there is no available treatment for the syndrome. The failure of clinical trials exploring pharmacological therapies for ARDS has been attributed to incomplete understanding of the pathogenesis and heterogeneity of the syndrome. As examples of the heterogeneity of ARDS, our recent work has identified differential outcomes of patients with ARDS depending on whether hypoxemia is rapidly improving or persistent severe or associated with non-identifiable risk factors or associated with neutropenia. It is advocated that the heterogeneity of ARDS can be tangled by a precision approach, which identifies endotypes of ARDS; i.e., subtypes characterized by a distinct biological profile that might share mortality risk, clinical course, or treatment responsiveness. Notwithstanding their contributions, current research efforts on endotyping ARDS might be limited by the fact that they are based on the current conceptual framework of the syndrome, which has been widely questioned. Indeed, for reasons such as high interobserver variability of radiological criteria of ARDS and exclusion of patients requiring high-flow nasal oxygen, influential experts have even suggested to completely abandon the term. Objective: Accordingly, in the current study, we attempt to perform endotyping of critically ill patients presenting in the emergency department with de novo AHRF, which is a simpler and more reliable phenotype than ARDS. The approach for endotyping will be dynamic rather than static; i.e, two blood samples with a 24-hour interval will be used for endotyping to trace trajectories of biomarkers (over 1500 unique human proteins). In addition, we attempt to identify what clinical, radiological, physiological and biological variables collected early in the course of AHRF correlate with subsequent mortality and/or persistent severe hypoxemia. Thus, the research protocol is organized as 3 aims. Aim#1 will organize a registry and biobank of critically ill patients presenting in the emergency department with de novo AHRF. Aim#2 will build a predictive model to identify what variables among those collected in Aim#1 are associated with subsequent mortality and/or persistent severe hypoxemia. Aim#3 will use an agnostic discovery approach to explore novel proteomic biomarkers-based dynamic endotypes in critically ill patients presenting in the emergency department with de novo AHRF. Also, Aim#3 will create a multiprotein model of biomarkers associated with subsequent mortality and/or persistent severe hypoxemia and will determine whether inclusion of this multiprotein panel in the predictive score developed in Aim#2 improves risk prediction.

Official Title
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EndotyPIng PreHospitAl de Novo Acute hYpoxemic Respiratory Failure

Conditions
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Acute Hypoxemic Respiratory Failure, Acute Respiratory Distress Syndrome

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients (aged >18 years) presenting in the emergency department De novo acute hypoxemic respiratory failure (requiring oxygen flow rate of 5 liters per minute or more to maintain SpO2 of 90% or more) Exclusion Criteria: Age <18 years Not admitted to the hospital Postoperative acute respiratory failure (within one week from surgery) Chronic hypoxemic respiratory failure (requiring long term oxygen therapy at home) Hypercapnic respiratory failure Transferred from another hospital or facility Pregnant women Admitted to the hospital purely to facilitate comfort care Lack of informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients with de novo acute hypoxemic respiratory failure<br>We will consider for inclusion patients presenting in the emergency department with de novo acute hypoxemic respiratory failure (AHRF). De novo AHRF is defined as the requirement of oxygen flow rate of 5 liters per minute or more to maintain SpO2 of 90% or more in a patient who does not receive long term oxygen therapy. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identification of dynamic endotypes of acute hypoxemic respiratory failure | Mutually exclusive subgroups of patients (clusters) characterized by a distinct biological profile that might share mortality risk, clinical course, and/or treatment responsiveness. | Until death or hospital discharge, assessed up to 28 days following presentation to the emergency department | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality | To determine what variables among those collected, including protein biomarkers, are associated with subsequent all-cause mortality. | Until death or hospital discharge, assessed up to 28 days following presentation to the emergency department | 
| Persistent severe hypoxemia | To determine what variables among those collected, including protein biomarkers, are associated with persistent severe hypoxemia. We will consider that persistent severe hypoxemia is present in endotracheally intubated individuals receiving positive pressure ventilation and having a PaO2:FiO2 ratio of equal to or less than 100 mmHg at 48 hours following intubation. | Until 28 days following presentation to emergency department | 
| Intensive care unit-free days | Intensive care unit-free days are calculated by the number of days in the first 28 days following presentation in the emergency department that a patient is alive and not in the intensive care unit. | Until 28 days following presentation to emergency department | 
| Vasopressor-free days | Vasopressor-free days are calculated by the number of days in the first 28 days following presentation in the emergency department that a patient is alive and not receiving vasopressors. | Until 28 days following presentation to emergency department | 
| Ventilator-free days | Ventilator-free days are calculated by the number of days in the first 28 days following presentation in the emergency department that a patient is alive and not on a ventilator. | Until 28 days following presentation to emergency department | 
| Continuous renal replacement therapy-free days | Continuous renal replacement therapy-free days are calculated by the number of days in the first 28 days following presentation in the emergency department that a patient is alive and not receiving continuous renal replacement therapy. | Until 28 days following presentation to emergency department | 
| Bacteremia | Bacteremia is determined by a positive blood culture. | Until 28 days following presentation to emergency department | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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emergency department, critical illness, intensive care unit, endotypes, phenotypes, trajectory, mechanical ventilation