Highlight
A pooled analysis of 30,516 mechanically ventilated critically ill patients found that, at the same tidal volume normalized to predicted body weight, female patients had a higher risk of elevated driving pressure than male patients.
Female patients also had smaller CT-measured anatomical and aerated lung volumes at the same predicted body weight, supporting the concern that the conventional predicted body weight equation may overestimate effective lung size in women.
The excess risk of high driving pressure among females was associated with higher 28-day mortality, with mediation analysis suggesting that injurious ventilator mechanics explained a measurable portion of this mortality gap.
The findings strengthen the case for more personalized ventilation strategies, particularly approaches that incorporate driving pressure and functional lung size rather than relying solely on predicted body weight.
Background
Low tidal volume ventilation is a cornerstone of modern intensive care. In acute respiratory distress syndrome (ARDS), and increasingly across broader populations of invasively ventilated patients, clinicians are taught to limit tidal volume to reduce ventilator-induced lung injury. The traditional bedside method is to scale tidal volume to predicted body weight, or PBW, rather than actual body weight. PBW is derived from sex and height, based on the premise that lung size tracks more closely with stature than with total mass.
This approach has become deeply embedded in daily practice, trial design, ventilator protocols, and quality metrics. Yet the PBW equation is a surrogate, not a direct measure of lung size. It assumes that two patients with the same sex and height have broadly similar pulmonary dimensions and therefore should tolerate similar tidal volumes per kilogram PBW. Over time, several clinicians and investigators have raised concerns that this simplification may not hold equally across sexes, particularly in critical illness where the “baby lung” concept applies. In ARDS and related syndromes, the portion of lung available for ventilation can shrink substantially, meaning the relevant target is not theoretical whole-lung size but functional aerated lung volume.
Sex-based disparities in mechanical ventilation have drawn growing attention. Women have often been reported to receive higher tidal volumes relative to PBW when height is inaccurately measured or PBW is estimated incorrectly. The current study asks a more foundational question: even when clinicians use PBW correctly, does the equation itself systematically overestimate lung size in female patients? If so, a woman and a man ventilated at the same ml/kg PBW may not be receiving an equivalent physiological dose of stretch.
Study Design
Von Wedel and colleagues addressed this question using a large, multi-source analysis that combined data from ten randomized controlled trials and two real-world retrospective clinical datasets. The overall cohort included 30,516 mechanically ventilated critically ill patients, of whom 39.4% were female. This design allowed the investigators to examine the issue across both rigorously characterized trial populations and more heterogeneous real-world practice.
The analysis focused on three linked questions. First, among patients receiving comparable tidal volumes standardized to PBW, were female patients more likely than male patients to experience high driving pressures? Driving pressure, usually defined as plateau pressure minus positive end-expiratory pressure, is widely used as a marker of dynamic lung stress and has repeatedly been associated with mortality in ventilated patients.
Second, did female and male patients with the same PBW differ in anatomical or functional lung size? To address this, the investigators evaluated clinically relevant measures of lung volume, including computed tomography-based measurements of total anatomical lung volume and aerated lung volume.
Third, could differences in driving pressure help explain sex differences in short-term outcomes, specifically 28-day mortality? The abstract reports a mediation analysis examining how much of excess mortality among female patients might be attributable to the higher risk of injurious driving pressure under PBW-based ventilation.
The key comparator was male versus female patients ventilated at comparable ml/kg PBW. The principal endpoint highlighted in the abstract was the occurrence of high driving pressure, defined as at least 15 cmH2O. The study also assessed mortality and imaging-based lung volume metrics.
Key Findings
Higher risk of elevated driving pressure in female patients
The central result is clinically striking. At comparable tidal volumes standardized to PBW, female patients had a 4.2% higher absolute risk of high driving pressures, with a 95% confidence interval of 3.2 to 5.3. The adjusted odds ratio was 1.26, with a 95% confidence interval of 1.19 to 1.33, and the association was highly statistically significant at p less than 0.001.
In practical terms, this means that when clinicians followed a PBW-based framework and delivered what would conventionally be considered equivalent lung-protective tidal volumes, women still experienced less favorable respiratory mechanics. Because driving pressure reflects the pressure needed to deliver a tidal breath into the available respiratory system, a higher value at the same nominal ml/kg PBW strongly suggests that the delivered breath is larger relative to the functional lung available for inflation.
This point is important. A tidal volume of 6 ml/kg PBW may be “protective” on paper, yet if PBW overestimates the patient’s true effective lung size, then that tidal volume may still impose excessive strain. The study therefore challenges the assumption that PBW is a biologically equivalent denominator across sexes.
Imaging evidence supports smaller lung volumes in women at the same PBW
The physiological signal was reinforced by imaging data. At the same PBW, female patients had lower anatomical lung volumes by 343 ml on average compared with male patients, with a 95% confidence interval of minus 449 to minus 237 ml and p less than 0.001. Female patients also had lower aerated lung volumes by 188 ml, with a 95% confidence interval of minus 282 to minus 94 ml and p less than 0.001.
These are not trivial differences. Anatomical lung volume reflects the size of the thoracic pulmonary structure, while aerated lung volume more closely approximates the portion of lung available to receive the delivered tidal breath. A smaller aerated volume at the same PBW means that a standard ventilator setting could represent a larger fractional inflation in female patients. That creates a plausible mechanistic pathway toward higher driving pressure, greater cyclic strain, and ultimately more ventilator-associated injury.
The CT findings also matter because they move the discussion beyond bedside surrogates. The concern is not merely that women have different chest wall mechanics or a different prevalence of certain diagnoses. Rather, the study suggests a structural mismatch between PBW-based assumptions and actual lung dimensions in female critically ill patients.
Potential impact on mortality
The investigators report that the excess risk of high driving pressure among female patients mediated 8.4% of excess 28-day mortality, again with p less than 0.001. Mediation analysis does not prove causality in the same way that randomization does, but it offers a coherent explanatory model: part of the observed mortality difference may be explained by systematically less favorable ventilator mechanics under a one-size-fits-all PBW formula.
Even a modest mediated proportion can be clinically important at population scale, given the enormous number of patients exposed to invasive ventilation worldwide. If a commonly used dosing equation produces sex-linked differences in mechanical stress, the implications extend beyond individual bedside management to ICU protocols, trial methodology, and guideline language.
Clinical Interpretation
The study’s message is not that PBW should be abandoned outright, nor that sex-specific care in ventilation is entirely new. Rather, it suggests that PBW is an imperfect proxy and may be particularly problematic when treated as the sole anchor for tidal volume selection. For decades, clinicians have used PBW because it is simple, reproducible, and safer than actual body weight-based dosing. That practical advantage remains real. However, simplicity can conceal bias.
Driving pressure has emerged as a clinically meaningful complementary metric because it incorporates both the delivered tidal volume and the compliance of the respiratory system. If female patients more often reach driving pressures at or above 15 cmH2O despite guideline-concordant ml/kg PBW, clinicians may need to titrate ventilation with greater attention to mechanics rather than assuming the PBW-derived number is intrinsically protective.
This is especially relevant in patients with ARDS, obesity, postoperative atelectasis, pneumonia, and mixed lung-chest wall pathology, where the relationship between stature and functional ventilated lung size becomes even less predictable. The study also underscores the practical importance of measuring height accurately and reassessing tidal volume when plateau pressure or driving pressure is unfavorable. A patient can satisfy a protocolized tidal-volume target and still be receiving a mechanically excessive breath.
How This Fits With Existing Evidence
The findings align with a broader body of ventilation research emphasizing mechanics over fixed dosing rules. Prior work, including analyses led by Amato and colleagues, has associated lower driving pressure with improved survival in ARDS, suggesting that the stress borne by the remaining functional lung may matter more than tidal volume alone. Likewise, the concept of the “baby lung,” developed through physiologic and imaging studies, established that diseased lungs behave as though they are much smaller than their anatomical appearance would suggest.
Guidelines from major critical care societies have historically recommended low tidal volume ventilation based on PBW because this approach reduced harm compared with larger conventional volumes. This new study does not undermine those guideline foundations; rather, it refines them. The question is no longer simply whether low tidal volume is better than high tidal volume. It is whether one PBW equation can adequately represent biologic lung size across diverse patients, especially women, under modern precision-oriented critical care.
The study also intersects with literature on sex disparities in ICU treatment. Some prior reports have suggested that women may be more likely to receive non-ideal ventilator settings for logistical reasons such as inaccurate height estimation, especially because shorter stature can lead to overestimation at the bedside. The current analysis goes further by arguing that even with appropriate application of the formula, the formula itself may still not normalize risk adequately.
Strengths and Limitations
The study has several notable strengths. First is scale: more than 30,000 ventilated patients across randomized trials and real-world datasets provide considerable statistical power and improve confidence that the signal is not idiosyncratic to a single center or disease subset. Second is triangulation: the authors did not rely only on ventilator variables but linked them to CT-derived anatomical and aerated lung volume measurements. Third is clinical relevance: high driving pressure and 28-day mortality are outcomes that matter directly to ICU practice.
Important limitations remain. The full article will be needed to assess cohort heterogeneity, consistency across the individual trials, handling of missing data, exact confounder adjustment, and definitions of respiratory variables. Driving pressure can be influenced by spontaneous effort, chest wall mechanics, sedation practice, and measurement technique. Without detailed protocol information, it is difficult to determine how uniform these measurements were across datasets.
In addition, mediation analyses are hypothesis-supporting rather than definitive proof of causation. Unmeasured confounding may persist, including differences in disease severity, ARDS prevalence, body habitus, chest wall elastance, or care processes not fully captured in the abstract. The imaging subgroup may also differ from the broader cohort in ways that affect generalizability.
Another limitation is implementation uncertainty. The study clearly identifies a problem, but the best bedside solution remains unsettled. Should clinicians lower starting tidal volume further in women? Should they use sex-specific correction factors? Should they prioritize driving pressure thresholds for all patients regardless of sex? These are related but distinct strategies, and each would ideally require prospective testing.
Practice Implications
For current practice, the most defensible takeaway is not to discard PBW but to avoid using it in isolation. Tidal volume should remain anchored to PBW as an initial safety framework, while respiratory mechanics are used to refine treatment. Particular vigilance may be warranted in female patients, especially shorter women, if driving pressures are elevated despite apparently guideline-concordant ml/kg PBW.
Reasonable bedside responses include confirming accurate measured height, reassessing plateau pressure and driving pressure after stabilization, considering lower tidal volume when mechanics are unfavorable, and evaluating recruitability, PEEP optimization, and patient-ventilator synchrony. In patients with severe ARDS or persistent high stress despite conventional settings, advanced individualized approaches such as esophageal pressure-guided strategies, prone positioning, and extracorporeal support remain relevant.
At a systems level, ventilator protocols and quality dashboards may need updating. Metrics based solely on ml/kg PBW could miss important sex-linked inequities in actual delivered lung stress. Incorporating driving pressure, when reliably measurable, may offer a more physiologically meaningful quality indicator.
Funding and ClinicalTrials.gov
The abstract provided does not list funding details or a ClinicalTrials.gov registration number for this pooled analysis. Because the work integrates data from ten randomized trials and two retrospective datasets, the original component trials may each have separate registrations and funding sources. Readers should consult the full publication for the complete funding statement, disclosures, and dataset-specific registration information.
Conclusion
This study delivers a clinically important challenge to a central assumption in mechanical ventilation. In a large cohort of critically ill ventilated patients, the standard predicted body weight equation appeared to overestimate lung size in female patients. As a result, women ventilated at the same ml/kg PBW as men were more likely to experience high driving pressure, and this disparity was associated with a measurable contribution to excess 28-day mortality.
The key message is not that lung-protective ventilation has failed, but that its current implementation may be insufficiently personalized. PBW remains useful, yet it should be regarded as a starting estimate rather than a complete physiologic prescription. For female critically ill patients in particular, driving pressure and other mechanics-based measures may better reflect the true dose of ventilation delivered to the lung.
If confirmed and operationalized in prospective studies, these findings could influence ventilator protocols, trial design, and guideline recommendations. More fundamentally, they illustrate a broader principle in critical care: standardization improves safety, but personalization is often required to achieve equity.
Citation
von Wedel D, Redaelli S, Fosset M, Pensier J, Shay D, Ahrens E, Wachtendorf LJ, Seibold EL, Suleiman A, Wu PW, Berkowitz SJ, Milá T, Balzer F, Costa EV, Jung B, Baedorf Kassis EN, Amato MB, Talmor D, Schaefer MS. The predicted body weight equation overestimates lung sizes of female, critically ill patients: an analysis of randomized, controlled trials and real-world clinical data. Intensive Care Medicine. 2026-05-07. PMID: 42096093. Available at: https://pubmed.ncbi.nlm.nih.gov/42096093/
Related literature: Amato MBP, Meade MO, Slutsky AS, et al. Driving pressure and survival in the acute respiratory distress syndrome. New England Journal of Medicine. 2015;372(8):747-755. Fan E, Del Sorbo L, Goligher EC, et al. An Official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guideline: Mechanical Ventilation in Adult Patients with ARDS. American Journal of Respiratory and Critical Care Medicine. 2017;195(9):1253-1263.