The review’s central reframing is subtle but consequential. Historically, adjuvant therapies were held back as rescue strategies, deployed only when refractory hypoxemia left clinicians with no other options. Current guidelines, by contrast, recommend applying them earlier in the disease course, reflecting the importance of minimizing stress and strain on the injured lung and potentially modulating the immune dysregulation that drives the syndrome. The authors organize commonly used adjuvants not by fashion or habit, but by the relative certainty of their utility and the frequency of their use—a taxonomy that reveals an uncomfortable truth: how often a therapy is used does not always match how well the evidence supports it.

At the top of the evidence hierarchy sits prone positioning, one of the most effective non-pharmacologic strategies for reducing mortality in moderate-to-severe ARDS. Its benefits extend well beyond improved oxygenation. Turning a patient face-down redistributes transpulmonary pressures more homogeneously across the lung, reduces overdistension of dorsal regions, recruits collapsed dependent lung tissue, and mitigates ventilator-induced lung injury. The PROSEVA trial demonstrated a substantial mortality reduction when prone positioning was applied early and for prolonged sessions in severe ARDS, and subsequent meta-analyses confirmed the benefit was greatest when it was combined with low-tidal-volume ventilation and sustained for more than sixteen hours per session. Despite this strong evidence and guideline endorsement, real-world adoption remains inconsistent, hampered by logistical demands and variability in clinician familiarity—a gap the authors describe as both common and serious.

Continuous neuromuscular blockade occupies a more contested middle ground. The physiological rationale is compelling: paralytic agents halt patient–ventilator dyssynchrony, eliminate excessively forceful spontaneous breathing efforts that can themselves injure the lung, control transpulmonary pressures, and reduce oxygen consumption. The ACURASYS trial showed improved survival and less barotrauma with a 48-hour course of early neuromuscular blockade in patients with moderate-to-severe but persistent ARDS. But the later ROSE trial, which applied the drugs slightly earlier in the disease course, found no mortality benefit. The discrepancy may reflect evolving practice—ROSE was conducted amid lighter sedation and higher PEEP, which may have blunted the incremental value of paralysis—or the fact that ACURASYS enrolled patients slightly later, enriching the study population for persistent, harder-to-treat disease. Current guidance favors short-course, targeted use, balanced against the risks of diaphragmatic inactivity and ICU-acquired weakness.

Conservative fluid management tells a different kind of story: modest evidence, near-universal adoption. Pulmonary edema worsens hypoxemia, decreases lung compliance, and amplifies ventilator-induced injury, so draining excess fluid with diuretics—or occasionally renal replacement therapy—directly supports the goals of lung-protective ventilation. The FACTT trial found that a conservative fluid strategy improved oxygenation, shortened the duration of mechanical ventilation, and reduced ICU length of stay, though it produced no mortality benefit. Even without a survival signal, the approach has become standard supportive care, fitting neatly into a broader philosophy of de-resuscitation: meticulous fluid stewardship for critically ill patients who have already received aggressive resuscitation, regardless of whether they carry an ARDS diagnosis.

Corticosteroids, meanwhile, have ridden decades of enthusiasm and disappointment. By attenuating the inflammatory cascade underlying ARDS, steroids promise reduced alveolar inflammation and less fibroproliferation. Recent trials and meta-analyses suggest early corticosteroids may shorten mechanical ventilation and ICU stays, particularly when initiated early in moderate-to-severe disease, and the COVID-19 pandemic cemented dexamethasone as standard care for severe hypoxemic viral pneumonia. Yet uncertainty persists over optimal dosing, duration, and applicability across etiologies. In late-phase ARDS, the evidence is mixed at best: an early trial of prolonged methylprednisolone in unresolving disease was followed by a larger study that failed to replicate a mortality benefit and raised a late mortality signal when treatment began more than fourteen days after ARDS onset. The authors conclude that steroids are best considered a phenotype-dependent therapy rather than a universally effective one, with trial heterogeneity likely reflecting biological differences among patients rather than absent efficacy.

Then there are the therapies that persist despite thin evidence. Inhaled pulmonary vasodilators—nitric oxide and epoprostenol—offer an elegant physiological fix for severe hypoxemia, selectively directing blood flow toward better-ventilated alveoli and reducing pulmonary vascular resistance. Studies consistently show transient oxygenation improvements, but none has demonstrated a mortality benefit, and harms such as renal dysfunction are documented. Guidelines do not recommend routine use. Nevertheless, inhaled vasodilators remain widely employed as short-term bridges to prone positioning, transfer, or escalation to extracorporeal support, and they may ease right ventricular afterload in acute cor pulmonale, though that indication has never been tested in randomized trials. Their persistence, the authors note, embodies the recurring tension between immediate physiological rescue and outcome-based evidence.

The deeper message of the review is that the right question is no longer whether an adjuvant works, but which therapy should be applied, in which patient, at what stage of disease, and to achieve which physiological objective. Timing matters as much as selection: prone positioning early and for long sessions in severe disease, neuromuscular blockade selectively when dyssynchrony and injurious breathing efforts dominate, fluids tightened once resuscitation is complete, steroids matched to inflammatory phenotype and etiology. The authors propose a framework mapping each adjuvant onto the evolving phases of ARDS, treating the syndrome as a moving target rather than a static diagnosis. Static classification at the bedside, they suggest, may ultimately matter less than dynamic reassessment throughout the illness.

Looking forward, the future of adjuvant therapy may be defined less by discovering new drugs than by deploying existing ones better. Advances in phenotyping—biological, physiological, and imaging-based—could identify which patients benefit from which interventions. The hyperinflammatory and hypoinflammatory subphenotypes described by Calfee and colleagues have already shown differential responses to several therapies, suggesting treatment effect varies with host biology rather than the syndrome label alone. Physiological phenotyping—respiratory mechanics, recruitability, respiratory drive, right ventricular function—may sharpen selection further. Equally important, the authors argue, is a willingness to de-adopt therapies lacking a strong evidence base. Adjuvants, they conclude, should not be regarded as rescue therapies of last resort but as targeted tools applied thoughtfully within a broader lung-protective strategy. The goal is deceptively simple to state and hard to achieve: the right adjuvant, for the right patient, at the right time.

Subject of Research: Adjuvant therapies for acute respiratory distress syndrome across the course of the disease

Article Title: Beyond the ventilator: deploying adjuvant therapies across the course of ARDS

Article References: Beyond the ventilator: deploying adjuvant therapies across the course of ARDS. (n.d.). https://doi.org/10.1007/s00134-026-08594-0

Image Credits: AI Generated

DOI: 10.1007/s00134-026-08594-0

Keywords: ARDS, mechanical ventilation, prone positioning, neuromuscular blockade, corticosteroids, conservative fluid management, inhaled pulmonary vasodilators, lung-protective ventilation, phenotyping, critical care, ventilator-induced lung injury, intensive care medicine

ARDS entered medical history in 1967, when Ashbaugh and colleagues described adults with severe hypoxemia, diffuse pulmonary infiltrates, reduced lung compliance and a clinical picture resembling the “shock lung” previously recognized after trauma. The syndrome is now understood as a form of acute inflammatory lung injury in which the alveolar-capillary barrier becomes abnormally permeable. Fluid floods the air spaces, surfactant function deteriorates, areas of lung collapse, and blood continues to pass through poorly ventilated regions. The result is profound impairment of oxygen transfer. Mechanical ventilation can sustain gas exchange, but excessive pressures and volumes may stretch vulnerable lung tissue, producing ventilator-induced lung injury. Extracorporeal support emerged as a way to interrupt that cycle by transferring part of the work of gas exchange from the damaged lungs to an external circuit.

The earliest systems were technically demanding and associated with substantial complications. In the 1970s, investigators used membrane lungs to oxygenate blood outside the body for patients with severe post-traumatic respiratory failure. A landmark randomized study published in 1979, however, failed to demonstrate a clear survival advantage for extracorporeal membrane oxygenation in severe adult respiratory failure. At the time, equipment limitations, high anticoagulation requirements and inadequate ventilation strategies constrained the therapy. ECMO subsequently declined in adult practice for several decades, even as it became an important treatment for selected newborns and children. The field began to change when improved pumps, polymethylpentene oxygenators, safer vascular cannulation and more protective ventilator strategies made prolonged support more feasible.

The modern revival of adult ECMO was strongly influenced by the CESAR trial, published in 2009, which compared conventional treatment with referral to an ECMO-capable specialist center. The study showed a higher probability of survival without severe disability among patients managed through the specialist pathway, although the trial evaluated referral to a comprehensive center rather than ECMO alone. The 2009 H1N1 influenza pandemic then provided an unexpected global test of the technology. Hospitals in Australia, the United Kingdom, Italy and elsewhere reported that selected patients with otherwise fatal viral pneumonia could survive with ECMO. During the COVID-19 pandemic, international registry studies further demonstrated that VV-ECMO could support patients with severe viral ARDS, although outcomes worsened when systems became overwhelmed and patients were referred after prolonged mechanical ventilation or extensive secondary organ injury.

Venovenous ECMO is designed primarily for respiratory failure. Blood is drained from the venous circulation, propelled through an artificial lung where carbon dioxide diffuses out and oxygen enters, and returned to the right side of the heart. The patient’s own heart then circulates the oxygenated blood through the body. Unlike venoarterial ECMO, which can provide both cardiac and respiratory support, VV-ECMO does not directly replace the pumping function of the heart. Its principal value in ARDS is that it can maintain oxygen delivery while allowing clinicians to reduce ventilator intensity. Lower tidal volumes, lower driving pressures and reduced respiratory rates can limit mechanical stress on the remaining functional lung. In some patients, ECMO also permits prone positioning, spontaneous breathing strategies or carefully controlled near-apneic ventilation, although each approach requires specialized monitoring.

The review emphasizes that ECMO is not a universal treatment for every patient with hypoxemia. Candidates generally have severe, potentially reversible respiratory failure despite optimized conventional care, including lung-protective ventilation, prone positioning and appropriate treatment of the underlying cause. Clinicians must also consider the duration of mechanical ventilation, age, frailty, neurological status and the presence of irreversible disease affecting other organs. Registry analyses and prognostic models such as RESP, PRESERVE and ECMOnet can help structure assessment, but they cannot determine an individual patient’s outcome with certainty. Obesity alone should not automatically exclude a patient, and selected people with cancer or other complex conditions may benefit. Conversely, advanced multisystem organ failure, devastating brain injury or an inability to recover from the underlying disease may make ECMO medically inappropriate.

Once support begins, management extends far beyond the circuit itself. Ventilator settings must be adjusted to avoid continuing injury while ensuring sufficient gas exchange and preventing dangerous derecruitment. Blood flow, sweep gas, oxygen transfer, carbon dioxide removal and recirculation must be assessed together rather than treated as isolated variables. Anticoagulation is usually required because blood contacts artificial surfaces, yet anticoagulation increases the risk of bleeding. Large international studies have documented frequent hemorrhagic and thrombotic events, including cannula-site bleeding, gastrointestinal hemorrhage, intracranial bleeding, oxygenator clotting and circuit thrombosis. Neurological complications are particularly serious; rapid changes in carbon dioxide after ECMO initiation may alter cerebral blood flow and have been associated with brain injury. Infection, limb ischemia, hemolysis, kidney failure, pressure injuries and profound muscle weakness add to the burden of prolonged support.

Liberation from ECMO is another area in which practice is evolving. As the lungs recover, clinicians gradually reduce sweep gas and test whether the patient can maintain acceptable oxygenation and carbon dioxide levels with less extracorporeal assistance. Successful weaning depends on improving pulmonary compliance, gas exchange, respiratory muscle function and the condition of other organs. There is no single universally accepted weaning protocol, and an international survey published in 2026 highlighted continued variation between centers. The review also notes that prone positioning during VV-ECMO remains an active subject of research. The PRONECMO randomized trial found that prone positioning could be performed safely in experienced centers, but broader questions remain about which patients benefit most and whether the strategy improves survival rather than simply oxygenation.

ECCO₂R represents a different concept. Instead of providing enough blood flow to replace most pulmonary gas exchange, ECCO₂R uses a lower-flow extracorporeal circuit primarily to remove carbon dioxide. Because carbon dioxide is more easily removed than oxygen is added, the technology can operate through smaller vascular catheters and may be less invasive than full ECMO. The proposed benefit is “ultra-lung-protective” ventilation: clinicians could reduce tidal volume or airway pressure beyond conventional protective targets while using the circuit to prevent carbon dioxide accumulation. Early studies, including Xtravent and SUPERNOVA, demonstrated technical feasibility and the ability to lower ventilator intensity in selected patients. Yet physiological improvement has not consistently translated into better outcomes. In the REST randomized trial, ECCO₂R-facilitated lower tidal-volume ventilation did not reduce 90-day mortality in patients with acute hypoxemic respiratory failure, and bleeding and other device-related risks remained important concerns.

The future of extracorporeal lung support will therefore depend less on simply building more powerful machines than on identifying the right patient at the right moment. Newer ECCO₂R platforms are being evaluated in mild-to-moderate ARDS, while studies are exploring support before invasive mechanical ventilation, advanced imaging, biological phenotyping and artificial-intelligence-assisted prediction. Researchers are also examining right-ventricular injury, a complication of severe pulmonary vascular stress that may improve when VV-ECMO reduces hypoxemia and unloads the heart. At the same time, long-term follow-up is revealing that survival is only the beginning of recovery. Survivors may experience persistent weakness, impaired cognition, post-traumatic stress, depression, anxiety and new mental-health diagnoses. The central lesson of six decades is therefore both promising and cautionary: ECMO can create time for injured lungs to heal, but it cannot replace careful critical care, and its success must ultimately be measured by meaningful recovery after the circuit is removed.

Subject of Research: Extracorporeal lung support for acute respiratory distress syndrome, including venovenous ECMO and ECCO₂R

Article Title: 60 years of ARDS and the evolution of extracorporeal lung support – from ECMO to ECCO₂R

Article References: Fernando SM, Brodie D, Slutsky AS, et al. “60 years of ARDS and the evolution of extracorporeal lung support – from ECMO to ECCO₂R.” Intensive Care Medicine (2026).

Image Credits: AI Generated

DOI: 10.1007/s00134-026-08533-z

Keywords: Acute respiratory distress syndrome; extracorporeal life support; venovenous ECMO; extracorporeal membrane oxygenation; ECCO₂R; respiratory failure; lung-protective ventilation