Identifying Clinical Research Priorities in Adult Pulmonary and Critical Care. NHLBI Working Group Report

Abstract

Preventing, treating, and promoting recovery from critical illness due to pulmonary disease are foundational goals of the critical care community and the NHLBI. Decades of clinical research in acute respiratory distress syndrome, acute respiratory failure, pneumonia, and sepsis have yielded improvements in supportive care, which have translated into improved patient outcomes. Novel therapeutics have largely failed to translate from promising preclinical findings into improved patient outcomes in late-phase clinical trials. Recent advances in personalized medicine, "big data," causal inference using observational data, novel clinical trial designs, preclinical disease modeling, and understanding of recovery from acute illness promise to transform the methods of pulmonary and critical care clinical research. To assess the current state of, research priorities for, and future directions in adult pulmonary and critical care research, the NHLBI assembled a multidisciplinary working group of investigators. This working group identified recommendations for future research, including 1) focusing on understanding the clinical, physiological, and biological underpinnings of heterogeneity in syndromes, diseases, and treatment response with the goal of developing targeted, personalized interventions; 2) optimizing preclinical models by incorporating comorbidities, cointerventions, and organ support; 3) developing and applying novel clinical trial designs; and 4) advancing mechanistic understanding of injury and recovery to develop and test interventions targeted at achieving long-term improvements in the lives of patients and families. Specific areas of research are highlighted as especially promising for making advances in pneumonia, acute hypoxemic respiratory failure, and acute respiratory distress syndrome.

Keywords: acute respiratory failure; clinical trials; mechanical ventilation; pneumonia; sepsis.

Figure 1.

Relationships between overall risk, disease-attributable risk, and treatment-responsive risk. The x-axis displays, for a theoretical population of critically ill patients with a disease of interest, each patient’s predicted risk of death, ranging from 0% (will almost certainly survive) to 100% (will almost certainly die). The y-axis displays the observed percentage of patients who die, ranging from 0% (no patients died) to 100% (all patients died). The light gray shading denotes the deaths that were caused by the disease of interest (disease-attributable risk). The medium gray shading denotes deaths that were caused by comorbidities or concurrent organ failures rather than the disease of interest. The dark gray denotes deaths prevented by treatment. (A) A disease-specific treatment will generally be able to prevent more deaths among patients who have a greater overall risk of death (prognostic enrichment) and whose risk of death is primarily due to the disease being treated rather than comorbidities or concurrent organ failures. (B) A specific therapy may have a greater effect on outcomes in a highly treatable disease compared with a poorly treatable disease. Which patients respond to a specific treatment depends on the mechanism of action and the biology of the disease. (C) The probability of responding to a specific treatment might be greatest among patients at high overall risk or low overall risk, or it might be completely independent of overall risk. Disease-specific treatments would generally be expected to prevent deaths resulting from the disease of interest (light gray), whereas some supportive therapies might be expected to prevent deaths resulting from the disease of interest (light gray) and deaths resulting from comorbidities or concurrent organ failures (medium gray).