In the Journals

Personalized mechanical ventilation fails to reduce mortality in ARDS

In patients with acute respiratory distress syndrome, personalizing mechanical ventilation based on lung morphology did not decrease mortality at 90 days, according to data published in The Lancet Respiratory Medicine.

In the multicenter, stratified, parallel-group, single-blind, randomized controlled LIVE trial, Jean-Michel Constantin, MD, from the department of perioperative medicine at the University Hospital of Clermont-Ferrand, and colleagues randomly assigned adults with moderate to severe ARDS for less than 12 hours at 20 ICUs in France to a control intervention or a personalized ventilation strategy based on whether the patient had focal or non-focal disease.

The control intervention included a tidal volume of 6 mL/kg of predicted bodyweight and positive end-expiratory pressure selected according to a low PEEP and fraction of inspired oxygen table and encouragement of early prone position, regardless of lung morphology. The personalized ventilation strategy, which did account for lung morphology, included a tidal volume of 8 mL/kg, low PEEP and prone position for patients with focal ARDS and a tidal volume of 6 mL/kg as well as recruitment maneuvers and high PEEP for patients with non-focal ARDS.

Local investigators determined lung morphology using CT scan or chest X-ray when the severity of the patient precluded transport between hospitals, and images were reexamined a posteriori by three experts. Notably, CT scan was only used in 29% of the intervention group and 39% of the control group.

No difference in 90-day mortality

Of 400 patients included in the analysis, 196 were assigned the personalized intervention and 204 were assigned control. Ninety-day mortality — the study’s primary endpoint — did not differ significantly between the personalized intervention and control groups after adjustment for multiple variables in the intention-to-treat analysis (HR = 1.01; 95% CI, 0.61-1.66).

The researchers noted, however, that 21% of the overall study population had been misclassified. A prespecified analysis that accounted for classification by experts showed that patients in the personalized group vs. the control group had improved 90-day survival (HR = 0.58; 95% CI, 0.37-0.93). There was also a significant interaction between misclassification and randomized group allocation regarding the primary outcome (P < .001), such that, in a subgroup analysis, 90-day mortality was higher in the personalized group vs. the control group (HR = 2.8; 95% CI, 1.5-5.1) for misclassified patients and lower in the personalized group vs. the control group (HR = 0.6; 95% CI, 0.37-0.99) for correctly classified patients.

Additionally, in a per-protocol analysis, excluding misclassified patients from the personalized group, 90-day mortality decreased from 27% in the control group to 17% in the personalized group (HR = 0.6; 95% CI, 0.36-0.99).

The trial’s negative findings, Constantin and colleagues noted, are potentially attributable to the high proportion of patients whose lung morphology was misclassified, but they concluded with two observations.

“When lung morphology is correctly assessed, mortality might decrease with personalized strategies in patients with moderate-to-severe ARDS. However, when personalized ventilation is misaligned with lung morphology, mortality increases substantially, suggesting a harmful effect of open-lung ventilation in patients without alveolar recruitment,” they wrote.

Promise of personalized medicine

In a linked comment, Carolyn M. Hendrickson, MD, MPH, and Carolyn S. Calfee, MD, MAS, placed the findings into context.

“The results of this trial highlight both the promise and the potential pitfalls of personalized medicine in critically ill patients. On the one hand, the results of the subgroup analysis excluding patients who were misclassified raise the tantalizing possibility that personalization of ventilatory strategy might improve patient outcomes. At the same time, the challenges encountered in the protocol execution emphasize how the pursuit of matching therapy to phenotype might be compromised by the additional logistical burdens of both obtaining and interpreting diagnostic tests for phenotype classification,” they wrote.

Hendrickson and Calfee also noted that identifying phenotypes before randomization in a clinical trial is “a new frontier in ARDS clinical research,” adding that better understanding of how to define phenotypes and how to develop individualized therapeutic interventions is essential.

“Although the findings from the LIVE study are unlikely to change current clinical practice, this study is an important milestone in the efforts to advance the principles of precision medicine in the care of patients with ARDS,” they wrote. – by Melissa Foster

Disclosure s: This study was funded by the French Ministry of Health. Constantin reports he has received personal fees and non-financial support from Drager, GE Healthcare, Sedana Medical, Baxter and Amomed; personal fees from Fisher and Paykel Healthcare, Orion Philips Medical and Fresenius Medical Care; and non-financial support from LFB and Bird Corporation. Please see the study for all other authors’ relevant financial disclosures. Hendrickson reports no relevant financial disclosures. Calfee reports she has received grant funding from GlaxoSmithKline and Bayer, and she has consulted for Bayer, Roche/Genentech, Prometic, CSL Behring and Quark.

In patients with acute respiratory distress syndrome, personalizing mechanical ventilation based on lung morphology did not decrease mortality at 90 days, according to data published in The Lancet Respiratory Medicine.

In the multicenter, stratified, parallel-group, single-blind, randomized controlled LIVE trial, Jean-Michel Constantin, MD, from the department of perioperative medicine at the University Hospital of Clermont-Ferrand, and colleagues randomly assigned adults with moderate to severe ARDS for less than 12 hours at 20 ICUs in France to a control intervention or a personalized ventilation strategy based on whether the patient had focal or non-focal disease.

The control intervention included a tidal volume of 6 mL/kg of predicted bodyweight and positive end-expiratory pressure selected according to a low PEEP and fraction of inspired oxygen table and encouragement of early prone position, regardless of lung morphology. The personalized ventilation strategy, which did account for lung morphology, included a tidal volume of 8 mL/kg, low PEEP and prone position for patients with focal ARDS and a tidal volume of 6 mL/kg as well as recruitment maneuvers and high PEEP for patients with non-focal ARDS.

Local investigators determined lung morphology using CT scan or chest X-ray when the severity of the patient precluded transport between hospitals, and images were reexamined a posteriori by three experts. Notably, CT scan was only used in 29% of the intervention group and 39% of the control group.

No difference in 90-day mortality

Of 400 patients included in the analysis, 196 were assigned the personalized intervention and 204 were assigned control. Ninety-day mortality — the study’s primary endpoint — did not differ significantly between the personalized intervention and control groups after adjustment for multiple variables in the intention-to-treat analysis (HR = 1.01; 95% CI, 0.61-1.66).

The researchers noted, however, that 21% of the overall study population had been misclassified. A prespecified analysis that accounted for classification by experts showed that patients in the personalized group vs. the control group had improved 90-day survival (HR = 0.58; 95% CI, 0.37-0.93). There was also a significant interaction between misclassification and randomized group allocation regarding the primary outcome (P < .001), such that, in a subgroup analysis, 90-day mortality was higher in the personalized group vs. the control group (HR = 2.8; 95% CI, 1.5-5.1) for misclassified patients and lower in the personalized group vs. the control group (HR = 0.6; 95% CI, 0.37-0.99) for correctly classified patients.

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Additionally, in a per-protocol analysis, excluding misclassified patients from the personalized group, 90-day mortality decreased from 27% in the control group to 17% in the personalized group (HR = 0.6; 95% CI, 0.36-0.99).

The trial’s negative findings, Constantin and colleagues noted, are potentially attributable to the high proportion of patients whose lung morphology was misclassified, but they concluded with two observations.

“When lung morphology is correctly assessed, mortality might decrease with personalized strategies in patients with moderate-to-severe ARDS. However, when personalized ventilation is misaligned with lung morphology, mortality increases substantially, suggesting a harmful effect of open-lung ventilation in patients without alveolar recruitment,” they wrote.

Promise of personalized medicine

In a linked comment, Carolyn M. Hendrickson, MD, MPH, and Carolyn S. Calfee, MD, MAS, placed the findings into context.

“The results of this trial highlight both the promise and the potential pitfalls of personalized medicine in critically ill patients. On the one hand, the results of the subgroup analysis excluding patients who were misclassified raise the tantalizing possibility that personalization of ventilatory strategy might improve patient outcomes. At the same time, the challenges encountered in the protocol execution emphasize how the pursuit of matching therapy to phenotype might be compromised by the additional logistical burdens of both obtaining and interpreting diagnostic tests for phenotype classification,” they wrote.

Hendrickson and Calfee also noted that identifying phenotypes before randomization in a clinical trial is “a new frontier in ARDS clinical research,” adding that better understanding of how to define phenotypes and how to develop individualized therapeutic interventions is essential.

“Although the findings from the LIVE study are unlikely to change current clinical practice, this study is an important milestone in the efforts to advance the principles of precision medicine in the care of patients with ARDS,” they wrote. – by Melissa Foster

Disclosure s: This study was funded by the French Ministry of Health. Constantin reports he has received personal fees and non-financial support from Drager, GE Healthcare, Sedana Medical, Baxter and Amomed; personal fees from Fisher and Paykel Healthcare, Orion Philips Medical and Fresenius Medical Care; and non-financial support from LFB and Bird Corporation. Please see the study for all other authors’ relevant financial disclosures. Hendrickson reports no relevant financial disclosures. Calfee reports she has received grant funding from GlaxoSmithKline and Bayer, and she has consulted for Bayer, Roche/Genentech, Prometic, CSL Behring and Quark.

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