Forty years on, why are we still publishing extracorporeal carbon dioxide removal feasibility studies?

Extracorporeal carbon dioxide removal (ECCO₂R) was introduced over 40 years ago but still faces scrutiny through feasibility studies, the latest of which was recently published in Critical Care [1]. Perhaps this enduring curiosity highlights a problem with the name because the role of ECCO₂R is not simply to reduce carbon dioxide (CO₂) levels; rather, it enables more protective ventilator settings by decoupling CO₂ elimination from minute ventilation. In short, ECCO₂R is all about reducing the intensity of mechanical ventilation, but which patients and ventilator settings should we select for this?

ECCO₂R was first clinically applied by the late Professor Luciano Gattinoni in the 1980s to facilitate low-frequency ventilation in acute respiratory distress syndrome (ARDS) patients. [2] This early strategy didn’t show mortality benefits in a randomised control trial (RCT), likely because low-frequency ventilation could not adequately protect against excessive airway pressures and tidal volumes and because of significant complications (mainly severe haemorrhages) related to devices used at that time. [3] Subsequent research, however, showed lower tidal volumes (4–8 mL/kg ideal body weight [IBW]) could improve ARDS outcomes [4] by reducing ventilator-induced lung injury through minimised airway pressures. [5] This sparked interest in ultra-low tidal volume ventilation (≤ 4 mL/kg IBW) supported by ECCO₂R [6], known as “ultra-protective” ventilation, even though the only two RCTs to study these tidal volumes did not conclusively show they are protective. [7, 8]

The first of these studies, "Lower tidal volume strategy (≈ 3 mL/kg) combined with ECCO₂R versus 'conventional' protective ventilation (6 mL/kg) in severe ARDS study (Xtravent)," randomised 79 ARDS patients. [7] It fell short of its 120-patient recruitment goal after the Data Safety Monitoring Board (DSMB) advised discontinuation due to low likelihood of achieving a statistically significant difference, partially because mortality rates were low in both groups (17.5% intervention vs 15% control). The intervention used pumpless arteriovenous ECCO₂R (AV-ECCO₂R), which is only feasible in haemodynamically stable patients, excluding many critically ill ARDS patients and partly explaining the low mortality rates. Today, few intensivists would use pumpless AV-ECCO₂R in critically ill patients—even if they were hemodynamically stable—due to concerns about complications associated with femoral artery cannulation and the reluctance of many teams to employ prone positioning in this situation. This intervention improves mortality in moderately-severe ARDS [9], and generally, prone positioning is more easily performed with veno-venous, pump-driven, ECCO₂R devices. [10]

The second study, "Effect of lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal vs standard care ventilation on 90-day mortality in patients with acute hypoxemic respiratory failure" (REST) [8], enrolled 453 patients with hypoxemic respiratory failure (P:F < 150), randomising them to receive a tidal volume less than or equal to 3 mL/kg IBW, supported by a centrifugal ECCO₂R device (Hemolung, ALung Technologies), or conventional lung-protective ventilation. Like Xtravent, it was stopped early by the DSMB after patients in the intervention group experienced higher rates of intracranial haemorrhage (10 vs 1) and because no significant difference in mortality was anticipated with the continuation of the study. Of note, the blood flow of the device was limited to 350–450 ml/min, and the observed decrease in Vt (6.3–4.5 mL/ kg) and driving pressure (15–12 cmH2O) from baseline were modest, while increased respiratory rate and PaCO2 were observed.

Both RCTs demonstrated that the indiscriminate use of ultra-protective volumes does not improve outcomes and may even pose risks, perhaps because the two studies selected patients primarily based on oxygenation criteria. Selection based on measures of oxygenation alone may not reliably indicate those who might benefit from ultra-protective ventilation supported by ECCO₂R. The ideal candidates are patients in whom conventional lung protective ventilation leads to excessive airway pressures, risking the perpetuation of lung injury from overdistension of remaining healthy units despite optimal PEEP settings. [11] Reducing tidal volumes below 4 mL/kg IBW to obtain driving pressures below 10 cm H2O may be the only solution for these patients. [12] However, these tidal volumes approach dead-space volume, risking hypercapnia that exacerbates immunosuppression and right-heart strain. [6] While this may be tolerated through permissive hypercapnia, the approach has not been shown to reduce mortality in patients already receiving lung-protective ventilation. [13] Extracorporeal membrane oxygenation is another option, but it requires specialised teams to manage the high blood flow rates and thus isn’t available in all centres. [14] If proven efficacious, ECCO₂R may offer an alternative with blood flow rates similar to dialysis that can be used in ICUs with existing dialysis infrastructure. [6]

Monet et al.’s feasibility study just published in Critical Care reported 45 ECCO₂R sessions in 41 respiratory failure patients. [1] Only 40% of sessions achieved a tidal volume at or below 3 mL/kg IBW; notably, all but one of these used a high-blood-flow ECCO₂R device (> 1000 mL/min). However, these sessions successfully reduced mean driving-pressure from 20 to 10 cmH₂O, an outcome associated with a lower ARDS mortality risk. [15] Mechanical power also dropped from 28 J/min to 7 J/min, and all this was achieved without significant hypercapnia, underscoring the potential of efficient ECCO₂R devices in supporting meaningful ventilator adjustments.

Monet et al.’s findings suggest that ECCO₂R can indeed support additional ventilator adjustments in cases where conventional lung protective ventilation leads to high driving-pressures and mechanical power, and perhaps these are patients we should be targeting. Low-flow ECCO₂R devices (blood flow < 500 mL/min) may present a favourable risk–benefit ratio and technical ease of use but nevertheless challenge the clinician by providing less margin to derive the optimal ventilator settings. Although promising, this single-centre study, conducted over eight years, included only 45 ECCO₂R sessions, and only 40% had a meaningful reduction in driving-pressures, highlighting the limited number of patients who might benefit from ECCO₂R. It is important to note that the observed mortality rate among patients whose Vt was successfully reduced to < 3 ml/kg was 82%. Future RCTs on ECCO₂R may need to be multicentre, most probably targeting patients with high driving pressures and mechanical power, treating them with highly efficient ECCO2R devices and possibly be integrated within platform trials to investigate multiple interventions simultaneously.

No datasets were generated or analysed during the current study.

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MEC acknowledges support from the National Medical Research Council Clinician Scientist Award grant (MOH-000693-00) and the National Research Foundation Singapore under its Open Fund-Large Collaborative Grant (MOH-001636) and administered by the Singapore Ministry of Health’s National Medical Research Council.

Authors and Affiliations

1. Department of Medicine, Division of Respiratory and Critical Care, National University Hospital, 1E Kent Ridge Road, Singapore, 119228, Singapore

   Matthew E. Cove

2. Institute of Cardiometabolism and Nutrition, INSERM Unité Mixte de Recherche (UMRS) 1166, Sorbonne Université, Paris, France

   Alain Combes

3. Service de Médecine Intensive-Réanimation, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, 75013, Paris, France

   Alain Combes

4. Institute of Intensive Care Medicine, University Hospital of Zurich, Zurich, Switzerland

   Matthias P. Hilty

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MC conceptualized the first draft, AC and MH provided critical revisions, and contributed to the final approval of the manuscript. All authors read and approved the final version of the manuscript.

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Correspondence to Matthew E. Cove.

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Cove, M.E., Combes, A. & P. Hilty, M. Forty years on, why are we still publishing extracorporeal carbon dioxide removal feasibility studies?. Crit Care 29, 35 (2025). https://doi.org/10.1186/s13054-024-05213-6

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• Received: 05 December 2024

• Accepted: 09 December 2024

• Published: 20 January 2025

• DOI: https://doi.org/10.1186/s13054-024-05213-6

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Keywords

• Acute respiratory distress syndrome
• Mechanical ventilation
• Extracorporeal carbon dioxide removal
• Respiratory failure
• Lung protective ventilation