With great interest we read the recent article by Artzner et al. arguing for a paradigm change in the clinical management of patients with severe acute-on-chronic liver failure (ACLF-3) [1].

We would like to congratulate the authors for their thorough and balanced viewpoint and especially agree with them on the crucial role that critical care needs to have for patients with ACLF-3 in a bridge to early transplantation setting. As support measures, the authors mention the use of renal replacement therapy, vasopressors and mechanical ventilation to stabilize patients in order to enable a window of transplantability.

We would like to raise the question of what critical care physicians might offer these patients beyond basic organ support. Multiorgan failure in ACLF is characterized by excessive systemic inflammation that could represent an additional therapeutic target for extracorporeal strategies. However, their use in ACLF remains controversial as albumin dialysis did not improve short-term survival, neither using the MARS (RELIEF) nor the PROMETHEUS-system (HELIOS) [2].

It might be worth looking beyond ACLF to other diseases with excessive systemic inflammation and multiorgan failure—e.g., septic shock and acute liver failure (ALF).

Therapeutic plasma exchange (TPE) is an extracorporeal strategy utilizing a profoundly different biological approach than the adsorptive strategies, which are all centered at removing injurious mediators. The rationale behind TPE rather follows the idea of combining, such as the removal of excessive injurious mediators with the replacement of diminished protective factors (Table 1) [3].

Table 1 Molecular mechanisms targeted by therapeutic plasma exchange (TPE) in critical illness associated with systemic inflammation
Full size table

Our group could demonstrate in patients with septic shock, that TPE effectively removes proinflammatory cytokines, endothelial- and glycocalyx destabilizing factors (e.g., angiopoietin-2, heparanase-1) as well as molecules involved in intravascular clotting and disturbance of the microcirculation (von Willebrand factor antigen, D-dimers) [3]. At the same time, the exchange of septic plasma with that from healthy donors leads to a replenishment of protective but depleted factors involved in anti-inflammatory processes (immunoglobulins), in endothelial stabilization (angiopoietin-1, heparanase-2) and in anti-coagulation (antithrombin-III, protein C, ADAMTS-13) [3]. In a recent trial, additive TPE was associated with rapid hemodynamic improvement in patients with severe refractory septic shock [4]. In ALF, high-volume TPE did not only improve transplant-free survival but also significantly reduced systemic inflammatory response syndrome (SIRS) and multiorgan dysfunction [5].

The APACHE trial is currently ongoing to determine the efficacy and safety of TPE in patients with ACLF (NCT03702920). Although we eagerly await the results, from an intensivist’s point of view the trial design unfortunately has an important shortcoming: human albumin instead of human plasma is used as the replacement fluid, which deprives TPE of the major potential to replace protective factors and, in the worst case, represents a safety issue in the case of already pronounced coagulopathy.

Who, if not intensivists—who are used to care for all organ systems holistically at the same time—should be able to bridge the gap across different critical illness entities such as ACLF, ALF and septic shock to find common ground in establishing more causative stabilization approaches to be offered to our patients?