Is ARDS a Preventable Disease? From Iatrogenic Injury to Phenotype-Targeted Protection

Subtitle: To what extent do our ICU practices actually prevent lung injury — and why does pharmacological prevention still disappoint?

The clinical question

How many of our patients who develop acute respiratory distress syndrome (ARDS) are victims of our own mistakes? We have fundamentally transformed our ventilation, transfusion and fluid management practices — but have these efforts translated into a tangible reduction in ARDS? And why do pharmacological prevention trials consistently fail?

The review in brief

In this narrative review published in Intensive Care Medicine on 8 June 2026, Yadav and colleagues ask, in the 60th year since ARDS was first described, whether the disease can be prevented.¹ Written by three experienced researchers from Mayo Clinic and the University of Minnesota, the paper synthesises clinical trials, population-based epidemiological data, implementation research and biological subphenotyping studies through the framework of the “multiple hit hypothesis”.

The authors consider ARDS cases in two main phenotypes: iatrogenic (hospital-acquired) and non-iatrogenic. On the iatrogenic side, the review reports striking successes: male-predominant donor plasma policies have dramatically reduced transfusion-related acute lung injury (TRALI), and lung-protective ventilation started in the emergency department and operating room has lowered both ARDS incidence and mortality. When bundled approaches combining restrictive transfusion and fluid management, aspiration precautions and early antimicrobial therapy were added, iatrogenic lung injury declined markedly.

In non-iatrogenic ARDS the picture is different. Pharmacological prevention trials in unselected populations have consistently failed. The authors emphasise that biologically distinct subphenotypes underlie this, each of which may respond differently — even oppositely — to the same intervention. Moreover, the population-attributable fraction of deaths due to ARDS turned out to be more modest than expected, suggesting that successful prevention may not produce a proportional improvement in mortality.

Interpreting the findings

The review offers both a balance sheet and a forward-looking road map for ARDS prevention. Much of it is consistent with current guidelines — but with a critical addition: it also tries to explain why we have not yet succeeded.

On lung-protective ventilation the path is clear. The ARDS Network trial published in 2000 showed that low tidal volume ventilation reduced mortality by about 9 percentage points,² and that result remains the cornerstone of every guideline today. The review takes this a step further, reporting that ARDS development itself may be prevented when protection starts before the ICU — in the emergency department or the operating room, right after intubation. It is a concrete reminder that tidal volume and plateau pressure targets should be known wherever the decision to intubate is made.

On pharmacological prevention there is an ongoing disappointment. Aspirin, statins, antioxidants and various immunomodulators have been tested repeatedly in unselected ARDS populations; the results have been inconsistent or negative. The review’s biological subphenotype argument is clarifying here: the hyperinflammatory/hypoinflammatory phenotype distinction developed by Calfee and colleagues since 2014³ shows that the same clinical diagnosis of ARDS hides fundamentally different biological processes. A single agent given to an unselected population inevitably produces a “mixed” signal. This framework also explains why biomarker-guided patient selection is increasingly central in ARDS research.

What does it mean at the bedside?

1. Start lung-protective ventilation early. The protective window is clearly the emergency department and operating room. In every patient you intubate — whatever the diagnosis — a target of 6 mL/kg ideal body weight and a plateau pressure ≤30 cmH₂O should be in place within the first hour.
2. Stay vigilant for TRALI. The change in donor policy is a remarkable success, but careful transfusion decisions protect that gain. “When in doubt, I give it” should be replaced on every round with “is it really necessary?”.
3. Apply the prevention bundle as a whole. Aspiration precautions + restrictive fluid and transfusion management + early antibiotics together achieve more than the sum of their parts. In ICUs with a high burden of neurological and elderly patients, as in many units in Turkey, bedside aspiration protocols are especially important.
4. Do not start pharmacological agents to prevent ARDS. There is no reliable evidence supporting statins, aspirin or antioxidants for this purpose. Every agent added without justification means both additional risk and unnecessary cost.
5. Phenotyping is entering the research agenda. Subphenotyping with biomarkers such as IL-8, PAI-1 and protein C is not yet in routine use; however, prospective data collection in university centres could help us understand local patient characteristics and why unselected trials fail.

Limitations and caveats

The narrative review format is itself a limitation: unlike a systematic review or meta-analysis, study selection and interpretation inevitably reflect the authors’ perspective. All three authors have been active in ARDS prevention programmes for decades; this expertise brings depth but also carries the risk that positive findings are prioritised.

The population-attributable fraction argument — the idea that the net contribution of ARDS to mortality is modest — is debated. Some researchers argue that this interpretation could understate the clinical value of ARDS prevention and pave the way for resources to be diverted away from the field.

Finally, most of the evidence base of the review comes from high-income countries. Generalisation to ICU settings with markedly different resources, patient demographics and infection profiles, including Turkish ICUs, should be made with caution.

Conclusion

Sixty years of accumulated work have brought meaningful progress in preventing iatrogenic ARDS — above all through lung-protective ventilation and transfusion policy. In non-iatrogenic lung injury, however, pharmacological prevention keeps hitting the wall of biological heterogeneity. The data point to a future built on phenotype-guided, individualised interventions and on the systematic implementation of evidence-based prevention bundles.

References

1. Yadav H, Marini JJ, Gajic O. Is acute respiratory distress syndrome a preventable disease? Intensive Care Med. 2026;52(9):1827-1832. doi:10.1007/s00134-026-08493-4
2. ARDS Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1301-1308. doi:10.1056/NEJM200005043421801
3. Calfee CS, Delucchi K, Parsons PE, et al. Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials. Lancet Respir Med. 2014;2(8):611-620. doi:10.1016/S2213-2600(14)70097-9

Doç. Dr. Serdar Efe — Intensive Care Quality Platform