Key lessons
-
Personalized medicine in ARDS is inherently challenging because of heterogeneous etiology and pathophysiology
-
ARDS research need not focus exclusively on novel investigational therapies, as repurposing drugs that have been studied in untargeted/unenriched populations could be just as innovative and promising, including for COVID-19 ARDS
-
Opportunities for targeting therapies include timing, clinical phenotypes, and biologic phenotypes
-
Adaptive clinical trial design offers the chance to investigate multiple therapies quickly and flexibly
-
Supportive interventions, such as ventilator management and fluid strategy, can also potentially be personalized
-
Though existing drugs and supportive care strategies may be repurposed/targeted, novel therapies are also on the horizon
Introduction
Targeting supportive therapy: personalized ventilator management
Parameter and study | Key contribution |
---|---|
Tidal volume | |
Hager et al. [92] | Reanalysis of the ARDSNet tidal volume trial demonstrated plateau pressure below 30 cm H2O was associated with additional improvement in survival, raising the possibility of residual VILI despite current standard-of-care low tidal volume ventilation |
Amato et al. [13] | Reanalysis of several clinical trials demonstrated changes in airway driving pressure mediated effects of tidal volume (and PEEP) on mortality, suggesting driving pressure may be a useful metric for individualizing tidal volume to patient-specific mechanics |
Pereira Romano et al. [19] | Pilot clinical trial demonstrated feasibility of a driving pressure-limited strategy without ECMO, laying the groundwork for a future trial of individualized tidal volumes |
PEEP | |
Single and multi-center trials, respectively, that demonstrated PEEP individualized to esophageal pressure, an estimate of pleural pressure, improved adjusted survival compared to an empirical low-PEEP strategy, but did not affect survival compared to an empirical high-PEEP strategy | |
Alveolar recruitment for ARDS trial (ART) [21] | Multicenter trial demonstrated a stepwise recruitment maneuver combined with PEEP titrated to highest respiratory system compliance, compared to an empirical low-PEEP strategy, increased mortality; interpretation of the PEEP effect is limited by the aggressive, prolonged exposure to extremely high airway pressures during the incremental/decremental recruitment maneuver |
LIVE trial [23] | Multicenter trial demonstrated tailoring PEEP to radiographic findings (higher PEEP in patients with non-focal opacities, lower PEEP if focal opacities) did not improve survival compared to an empirical low-PEEP strategy, although misclassification of radiographs limits interpretation of findings |
Weighting relative importance of ventilator parameters | |
Gattinoni et al. [27] | Cohort study proposed mechanical power delivered by the ventilator, combining several ventilator parameters into a unifying metric to quantify VILI risk |
Costa et al. [29] | Cohort study that concluded driving pressure and respiratory rate were the key parameters of mechanical power that influence mortality, also suggesting the effect on mortality of each 1 cm H2O increase in driving pressure was four times that of each 1 breath/min increase in respiratory rate |
Differential treatment responses in ARDS biologic phenotypes
New avenues for existing therapies: sepsis-related ARDS
Lessons from the COVID-19 pandemic
Studies | Date | Design | Participants | Interventions | Primary Outcome | Heterogeneity across subgroups | Comments |
---|---|---|---|---|---|---|---|
Non-COVID-19 ARDS studies | |||||||
Steinberg et al. [94] | 2006 | Country: USA Centers: 25 Placebo-controlled, double-blind 2 parallel groups | N = 180 (400 planned) Adults Persistent ARDS for 7 days at least and 28 days at most | Methylprednisolone bolus of 2 mg/kg followed by 0.5 mg/kg every 6 h for 14 days, 0.5 mg/kg every 12 h for 7 days, and then tapering of the dose Comparator: placebo | 60-day mortality rates 29.2 (95% CI 20.8–39.4) versus 28.6 (20.8–38.6), P = 1.00 | Methylprednisolone was associated with + 27% absolute difference in mortality rate in patients randomized after 14 days from onset of ARDS And + 26% in patients with low levels of procollagen peptide III in the bronchoalveolar lavage fluid | Sample size was changed from 400 to 180 owing to external information on baseline risk of death and low recruitment rate Methylprednisolone was associated with significantly more mechanical ventilation free days, and more risk of acquired muscle weakness |
Meduri et al. [95] | 2007 | Country: USA Centers: 5 Placebo-controlled, double-blind 2 parallel groups Sequential analyses | N = 91 (400 planed) Adults ARDS within 72 h of onset | Methylprednisolone bolus of 1 mg/kg followed by 1 mg/kg/24 h continuous infusion for 14 days, 0.5 mg/kg/24 for 7 days, 0.25 mg/kg/day for 4 days, 0.125 mg/kg/day for 3 days Comparator: placebo 2:1 scheme | The RR for extubation of improvement in Lung Injury Score by 1 or more point at study day 7 was 1.96 (1.16–3.30) in favor of methylprednisolone | Interaction of responses to treatment and adrenal status by Synacthen test could not be performed owing to small sample size | 36% of patients in the placebo group did received open label methylprednisolone |
Tongyoo et al. [96] | 2016 | Country: Thailand Centers 1 Placebo-controlled, double-blind 2 parallel groups | N = 206 (194 planned) Adults Septic shock and ARDS | Hydrocortisone, 200 mg/day in 4 bolus of 50 mg for 7 days Comparator: placebo | The RR of dying at 28-day mortality was 0.82 (0.50–1.34) in favor of hydrocortisone | There was no interaction between response to treatment and subgroups based on age or severity of illness | Effects of corticosteroids were consistent across all secondary outcomes without increased in the risk of adverse reactions except for the risk of hyperglycemia |
DEXA-ARDS [97] | 2020 | Country: Spain Centers: 17 Open-label 2 parallel groups | N = 277 (314 planned) Adults Moderate to severe ARDS | Dexamethasone 20 mg bolus daily to day 5, followed by 10 mg daily to day 10 | The mean number of ventilator-free days was 4.8 days [95% CI 2.57 to 7.03] higher in dexamethasone group than in controls At 60-day the between-group difference in mortality was − 15.3%; − 25.9 to − 4.9 in favor of dexamethasone | – | Trial stopped prematurely for low recruitment rate Benefits from corticosteroids were consistent across secondary outcomes |
COVID-19 studies | |||||||
RECOVERY [47] | 2021 | Country: UK Platform trial Multicenter, randomized Open-label | N = 6425 Adults Suspected or confirmed COVID-19 Hospitalized | Dexamethasone 6 mg/d orally or intravenously For 5 to 10 days Control: usual care | The age-adjusted rate ratio for 28-day mortality was 0.83; 95% CI 0.75–0.93 | On invasive mechanical ventilation, the RR was, 0.64; 95% CI 0.51–0.81) On oxygen without invasive mechanical ventilation, the RR was 0.82; 95% CI 0.72–0.94 No respiratory support at randomization, the RR was 1.19; 95% CI 0.92–1.55 | Trial stopped prematurely for efficacy |
CoDEX [98] | 2020 | Country: Brazil Centers: 51 Open-label | N = 299 (350 planned) Adults Moderate to severe ARDS Onset < 48 h before randomization Invasive Mechanical ventilation Probable or confirmed COVID-19 | Dexamethasone Intravenous bolus 20 mg/day for 5 days, then 10 mg/day for 5 days Control: usual care | The mean ventilator-free days was 6.6 (95% CI 5.0–8.2) in dexamethasone group versus 4.0 (95% CI 2.9–5.4) in controls The difference was 2.26; 95% CI 0.2–4.38, in favor of dexamethasone The RR for 28-day mortality was 0.86; 95% CI 0.64–1.15) | There were no evidence for interaction between response to treatment and age, severity of illness, degree of hypoxia, duration of disease prior to randomization, or vasopressor-dependency | Trial was stopped prematurely following external information from the RECOVERY trial |
CAPE COVID [99] | 2020 | Country: France Centers: 28 Embedded, randomized Double-blinded Placebo controlled | N = 256 (290 planned) Adults Admitted to ICU or intermediate care unit Oxygen ≥ 6 L/min Probable or confirmed COVID-19 | Hydrocortisone, continuous infusion for 8 days or 14 days 200 mg/day for 4 days or 7 days; 100 mg/day for 2 or 4 days, and 50 mg/day for 2 or 3 days Comparator: Placebo | The OR for 21-day mortality was 0.46 95% CI 0.20–1.04 | – | Trial was stopped prematurely following external information from the RECOVERY trial |
REMAP-CAP [100] | 2020 | Country: Europe, USA, Canada, Australia, New Zealand, Saudi Arabia Platform trial Centers, Platform trial Open-label Bayesian analyses | N = 403 ICU adults High-flow nasal oxygen with FIO2 ≥ 0.4 at ≥ 30 L/min, noninvasive or invasive Ventilatory support, or vasopressors Probable or confirmed COVID-19 | Hydrocortisone intravenously fixed 7-day course of 50 mg or 100 mg every 6 h) OR A shock-dependent course of 50 mg every 6 h when shock was clinically evident) Comparator: usual care | The median adjusted OR and Bayesian probability of superiority were 1.43 (95% CI 0.91–2.27) and 93% for fixed-dose hydrocortisone, respectively, and 1.22 (95% CI 0.76–1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone | – | Trial was stopped prematurely following external information from the RECOVERY trial |
MetCOVID [101] | 2020 | Country: Brazil Center, 1 Double-blinded Placebo 2 parallel groups | N = 416 (416 planned) ICU adults suspicion of COVID-19, SpO2 ≤ 94% with room air, required supplementary oxygen, or required IMV | Methylprednisolone intravenously 0.5 mg/kg twice daily for 5 days Comparator, Placebo | The OR for 28-day mortality was 0.92, 95% CI 0.67–1.28 | There was no evidence for interaction between response to treatment and age, level of respiratory support, biomarkers of inflammation | Post hoc analysis suggested survival benefit from MP in patients of > 60 years old whereas younger patients may have increased risk of death with MP |
GLUCOCOVID [102] | 2021 | Country: Spain Centers, 5 Open-label 2 parallel groups | N = 64 (180 planned) Adults Suspicion of COVID-19, disease duration < 7 days Moderate to severe ARDS CRP > 15 mg/L Or IL-6 > 20 pg/mL Or D-dimer > 800 ng/mL, or ferritin > 1000 mg/dL | Methylprednisolone intravenous 40 mg bid for 3 days, then 20 mg bid for 3 days Comparator: usual care | The age-adjusted RR for the composite of death, progression to ICU admission, or progression to NIV was 0.68, 95% CI 0.37–1.26, in favor of corticosteroids | There was no evidence for an interaction between treatment response and duration of symptoms prior to randomization | The study was stop prematurely following the release of the RECOVERY trial and the low recruitment rate |
Promising therapies in early ARDS: inhaled therapies
Novel therapies: mesenchymal stromal cells
Intelligent clinical trial design
Strategy | Type of heterogeneity | Specifics | Pros | Cons | Examples |
---|---|---|---|---|---|
Subgroup analysis | Any | Pre-specify subgroups for analysis on completion of traditional RCT | Acknowledges uncertainty about best matching of treatment to subgroup/phenotype | Inefficient; too many subgroups may result in false positives | Liu et al., activated protein C in ARDS [103] |
Prognostic enrichment | Severity | Restrict enrollment to patients with more severe ARDS (lower PaO2/FiO2 ratio) | Likely enhances ability to detect treatment response, as relative risk reduction translates into higher absolute risk reduction if mortality is high | Reduces generalizability; may miss benefit in milder ARDS | PROSEVA trial [104] |
Predictive enrichment | Biologic, physiologic, radiographic | Restrict enrollment to patients with specific abnormalities targeted by chosen therapy (e.g., inflammation of a certain level, for an anti-inflammatory therapy) | May identify treatment-responsive subset by better matching therapy with phenotype | Reduces generalizability; requires either understanding of or assumptions about best way to personalize treatment; no proof of “non-response” in excluded patients | RECOVERY tocilizumab trial [45] |
Explicit comparison of personalized versus non-personalized therapy | Any | Randomize patients to personalized arm (with specific therapies based on subgroup/phenotype) vs standard-of-care arm | Explicit test of whether personalized strategy improves outcomes; tests effectiveness as well as efficacy to some degree | Complexity of design; misclassification may bias toward null; requires either understanding of or assumptions about best way to personalize treatment | LIVE trial [23] |
Adaptive design | Any | Pre-specify subgroups and stratify randomization; adjust target population or randomization based on interim analyses of subgroup-specific results | Acknowledges uncertainty about best matching of treatment to subgroup/phenotype but with greater efficiency than standard RCT; allows “learning as you go” | Complexity of design; more sophisticated analytic approaches may be needed | Bhatt and Mehta (review) [105] |