On April 27-28, 2023, the National Heart, Lung, and Blood Institute (NHLBI), of the National Institutes of Health (NIH), convened a workshop, “Tackling Brain and Muscle Dysfunctions in ARDS Survivors”. The workshop brought together basic, translational, and clinical scientists as well patient representatives, to identify the critical knowledge gaps, key barriers, and research opportunities in understanding the pathophysiology and clinical management in brain and muscle dysfunctions in Acute Respiratory Distress Syndrome (ARDS) survivors.
ARDS is a devastating clinical syndrome that leads to acute respiratory failure and can result in death. ARDS is increasing in incidence, even before the COVID-19 pandemic which led to millions of cases of ARDS worldwide. Additionally, over the last five decades, there has been a concerted effort in improvements in general critical care and ventilator management with a concurrent reduction in mortality, from 80% in the initial reports to the current rate of 25% to 40%. This leads to a growing number of ARDS survivors. Unfortunately, these patients commonly suffer from lasting sequelae, including increased mortality after discharge, physical and cognitive impairment, and reduced quality of life.
ARDS and its associated conditions and treatments affect many organs in addition to the lung, both during the acute phase of illness and during recovery. Those surviving ARDS display a high prevalence of cognitive impairment: 70-100% at hospital discharge, 46-80% at 1 year, and 20% at 5 years. Clinically apparent skeletal muscle weakness occurs in up to 60% of critically ill patients. Survivors of ARDS also experience substantial impairments of body function, including muscle strength, walking capacity and/or physical activity, between 6 months and 2 years after discharge from the intensive care unit (ICU). More importantly, ARDS develops in 42% of patients presenting with COVID‐19 pneumonia, and COVID-19 survivors also develop fatigue or muscle weakness (37.5%) and cognitive impairment (17.1%). Thus, there is an unmet need in the clinical management of ARDS survivors and an urgent need for novel intervention strategies for these patients.
Although emerging data suggest that neuroinflammation and muscle wasting contribute to the brain and muscle dysfunction in ARDS survivors, the molecular mechanisms underlying these long-term health issues in ARDS survivors remain elusive. There is a critical knowledge gap in our understanding of the pathophysiology in this area. NHLBI convened this workshop with a panel of experts and stakeholders to seek inputs from the community to inform future clinical trials. Topics included clinical presentation, social determinants of health, pathogenesis and recovery, and interventions.
The workshop is relevant to NHLBI’s strategic goals to “Understand Human Biology”, “Reduce Human Disease”, and “Advance Translational Research”. It is responsive to NHLBI Strategic Vision Objectives 1-4.
- Capture the state of science as it relates to brain and muscle dysfunction following ARDS and critical illness.
- Evaluate critical knowledge gaps and key barriers.
- Identify research opportunities in understanding the pathophysiology in brain and muscle dysfunctions in ARDS survivors.
- Present high risk, high reward ideas to move the science forward in this field.
Presentations focused on four thematic areas:
- Clinical Presentation, Rigorous Measurements, and Social Determinants Of Brain and Muscle Dysfunctions.
- Pathogenesis and Recovery Of Neurocognitive Dysfunction.
- Pathogenesis and Recovery Of Muscle Dysfunction.
- Moving from Observation to Intervention.
Breakout room discussions were organized on cross-disciplinary themes:
- Cognitive impairment mechanistic advances.
- Cognitive impairment platform trials.
- Physical impairment mechanistic advances.
- Physical disability platform trials.
Overarching Goals: Workshop participants identified three overarching prospective milestones for medium to long term actions:
- Gain fundamental insights into the mechanistic underpinnings of cognitive and physical impairments following ARDS.
- Improve education and infrastructure for the continuity of care for ARDS and critical illness survivors.
- Advance clinical trial designs to effectively manage neurocognitive dysfunction and physical dysfunction in ARDS survivors.
Gaps and Opportunities: Workshop participants identified the following knowledge gaps, key barriers, and research opportunities to guide future investigations:
Mechanistic advances in cognitive impairment
- Update animal models to reflect clinical phenotypes that are identified in humans (e.g., ARDS phenotypes), despite the fact that we will never have an animal model that captures the same heterogeneity that we find in patients.
- Establish well-annotated biospecimen collections guided by Standard Operating Procedures (SOPs) to gather information at multiple timepoints across the continuum of critical illness and recovery.
- Define a set of core outcomes relevant to cognitive impairment emerging from human biospecimens and animal models.
- Emphasize the value of cerebrospinal fluid as a critical biospecimen to assess cognitive impairment in ARDS survivors.
- Need to compare patients across different trajectories of cognitive decline and recovery.
- Focus on both acute cognitive impairment (manifesting as delirium) and long-term cognitive impairment.
Cognitive impairment platform trials
A platform trial to study interventions targeting cognitive impairment in ARDS survivors should consider the following:
- Broaden inclusion criteria for critically ill patients, including various phenotypes such as sepsis and/or ARDS, invasive mechanical ventilation, respiratory failure or shock.
- Address equity and inclusion of populations traditionally underrepresented in clinical research as well as high-risk populations.
- Include populations such as those with pre-existing cognitive and functional impairment, and those with pre-existing mental health impairment.
- Design interventions that assess the value of spouse/family-centered empowerment and anticipatory guidance trials.
- Evaluate alternative therapeutic strategies to cognitive rehabilitation departing from pharmacologic therapy, for example those related to physical rehabilitation versus standard of care, or financial support versus no financial support.
- Factorial design with prioritized interventions.
- Propose high-risk projects as large consortiums may lead to underwhelming interventions.
- Enroll patients early and study interventions in both acute period and recovery period.
- Adopt Delphi process for selecting interventions.
- Introduce patient-centered outcomes such as performance after discharge (e.g., return to work) and capture long-term trajectories.
- Assess reverse translatable outcomes with long-term trajectories, including multiple brain domains (e.g., delirium, delirium/coma free days, severity, and data-driven subtypes of delirium).
- Monitor for safety signals such as post-traumatic stress disorder from electrical stimulation and aggressive rehabilitation.
- Capture pragmatic health status (telehealth, mobile-phlebotomist as operator), survival, length of stay, ventilator-free days, quality-of-life, biosamples (during hospitalization, post-hospitalization) including availability for basic/translational researchers to inform enrichment.
- Consider novel agents (e.g., anti-tau, agents that coach microglia to become more homeostatic, or IL-6 trans-signaling pathway inhibitor) in a platform trial.
- Statistical analysis
- Consider missingness, censoring, adaptive design, and Bayesian thinking.
Mechanistic advances in physical disability
- Study the role of specific mechanisms in physical disability. Possible mechanisms include protein synthesis/degradation, protein folding, post-translational modification, mitochondrial function, satellite cells, muscle-specific inflammation.
- Perform longitudinal time series assessments of muscular impairment up to 6 months after acute illness.
- Consider age as an important factor impacting frailty and physical disability following hospital discharge.
- Validate muscle biopsies as a biospecimen to study pathobiology and recovery.
- How do we connect the dots between molecular targets of muscle dysfunction and patient-centered outcomes (such as ability to ambulate independently or return to work)
- Which mechanistic findings identified in animal models translate to humans?
- Adopt reverse translation approaches to inform new directions of pre-clinical research.
- Understand the heterogeneity of weakness at a higher level of specificity than current definitions such as atrophy, myopathy, and neuropathy.
- Identify correlates between biomolecules and muscular function (e.g., motility), to inform, ideally at early stage of ARDS, subsequent efforts to minimize muscle atrophy during critical illness and recovery.
Physical disability platform trials
A platform trial to study interventions targeting physical disability in ARDS survivors should consider the following:
- Introduce inclusion criteria not restrictive to the Berlin criteria for ARDS, but inclusive of those at level of respiratory support.
- Allow for different baseline function evaluations and age to come into the trial but stratify interventions based on baseline function/ability.
- If based on recovery, interventions should be delivered early, later, or even post hospitalization.
- Implement follow-up strategies focused on long-term evaluation and with use of telemedicine, virtual communication, or field evaluations.
- Include both trials that could target lung injury resolution and those that directly target physical function.
- Address the ability to deliver novel therapeutic agents and environmental/exercise, comparative effectiveness.
- Tailor interventions based on patient’s baseline function/ability.
- Anti-inflammatory (drugs targeting the lung) that might also affect physical function.
- Consider impact of intervention on muscle loading domain (exercise, mass estimates, etc.).
- Direct muscle targeting interventions with novel or repurposed pharmacological agents that are being or have been tested in other diseases (e.g., cancer cachexia).
- Evaluate community based interventions or those focused on relevant social determinants of health such as social connectedness, economic stability, neighborhood and built environment among others.
- The primary outcome of a master protocol would need to be some outcome(s) that are patient centered, or related to feasibility and timing of assessments.
- Consider trajectories and return to baseline.
- Introduce implementation outcomes such as acceptability and feasibility of interventions. Consider adaptive or “personalized” outcome measures that are informed by personal values, social role, physical environment.
- Unpack if there are biological advantages to muscle atrophy in terms of short term survival that may impact efforts to minimize muscle atrophy during critical illness and recovery.
- Statistical analysis
- Consider missingness, censoring, adaptive design, Bayesian adaptive trial, and methods to minimize loss to follow-up.
The meeting participants are developing a workshop report, outlining the meeting’s main objectives, knowledge gaps, and future research opportunities that were identified at the workshop, for publication in a peer-reviewed journal.
- C. Terri Hough, MD, MSc, firstname.lastname@example.org, Oregon Health & Science University
- Timothy D. Girard, MD, MSCI, email@example.com, University of Pittsburgh
Speakers, Moderators, and Designated Writer
- Jane Batt, MD, PhD, firstname.lastname@example.org, University of Toronto,
- Sue C. Bodine, PhD, email@example.com, Oklahoma Medical Research Foundation,
- Bronwen Connolly, PhD, MSc, BSc(Hons), MCSP, firstname.lastname@example.org, Queen’s University Belfast, UK,
- Jason Doles, PhD, email@example.com, Indiana University School of Medicine,
- Jason R. Falvey, PT, DPT, PhD, firstname.lastname@example.org, University of Maryland School of Medicine,
- Lauren Ferrante, MD, MHS, email@example.com, Yale University School of Medicine,
- D. Clark Files, MD, firstname.lastname@example.org, Atrium Health Wake Forest Baptist,
- Michael Harhay, PhD, MPH, email@example.com, University of Pennsylvania,
- Kirsten Harrell, PsyD, firstname.lastname@example.org, Clinical Psychologist (retired),
- Joseph Hippensteel, MD, MS, email@example.com, University of Colorado Anschutz Medical Campus,
- Theodore "Jack" Iwashyna, MD, PhD, firstname.lastname@example.org, Johns Hopkins University,
- James C. Jackson, PsyD, email@example.com, Vanderbilt University School of Medicine,
- Meghan Lane-Fall, MD, MSHP, FCCM, firstname.lastname@example.org, University of Pennsylvania,
- Michelle Monje, MD, PhD, email@example.com, Howard Hughes Medical Institute, Stanford University,
- Marc Moss, MD, firstname.lastname@example.org, University of Colorado School of Medicine,
- Dale Needham, MD, PhD, email@example.com, Johns Hopkins University,
- Matt Semler, MD, MSCI, firstname.lastname@example.org, Vanderbilt University Medical Center,
- Shouri Lahiri, MD, email@example.com, Cedars Sinai Hospital,
- Lars Larsson MD, PhD, firstname.lastname@example.org, Bioclinicum Sweden,
- Jessica A. Palakshappa, MD MS, email@example.com, Wake Forest University School of Medicine,
- Carla Sevin, MD, firstname.lastname@example.org, Vanderbilt University School of Medicine,
- Tarek Sharshar PhD, email@example.com, the GHU-Psychiatry, Neuroscience of Paris,
- Benjamin Singer, MD, PhD, firstname.lastname@example.org, University of Michigan,
- Troy Stevens, PhD, email@example.com, University of South Alabama,
- Stephanie P. Taylor, MD, firstname.lastname@example.org, University of Michigan.