Editorial: terlipressin in patients with acute‐on‐chronic liver failure grade 3—too late?

The recent study by Wong et al1 was a post hoc analysis of the relationship between terlipressin for the treatment of hepatorenal syndrome (HRS) and respiratory failure in the CONFIRM trial.2 HRS has a particularly strong effect on survival and needs early specific pharmacological therapy, namely a combination of terlipressin and albumin.3 This has been already recommended in guidelines and has been in clinical use for more than a decade in Europe.4 However, in the US, terlipressin was not approved until the randomised placebocontrolled CONFIRM trial demonstrated clear benefit in HRS type 1,2 leading in September 2022 to its approval. The presence of HRS defines acuteonchronic liver failure (ACLF), a syndrome associated with acute decompensation of cirrhosis, organ dysfunction/failure(s) and a high short mortality.5 ACLF grades are defined by the number of organ failures; mortality increases with severity.5 In the CONFIRM study, 20% of patients had ACLF grade 3 (4– 6 organ failures). In this group, terlipressin was associated with the development of respiratory failure.1 Respiratory failure is a negative predictor in ACLF.5 Mechanical ventilation for airway protection, which is not defined as respiratory failure, also has a strong impact on survival. These reasons for intubation and mechanical ventilation are underestimated in the risk scores of patients with ACLF.6 Interestingly, SpO2 at baseline was an independent predictor of the development of respiratory failure. This suggests that, in these patients, there was pulmonary impairment at baseline that was aggravated by the administration of terlipressin. But why only in the terlipressin group? The European experience is that the response to terlipressin declines with increasing ACLF grade.7 Acute kidney injury (AKI) in patients with decompensated cirrhosis may have different phenotypes, with the HRS phenotype (AKIHRS) being one.3 However, distinguishing among different types of kidney injury is challenging. Therefore, terlipressin was not successful in all patients, probably due to the presence of acute tubular necrosis. However, overall, terlipressin reduced the probability of renal replacement therapy (RRT) as a primary endpoint. However, in terlipressintreated patients, volume overload may be more likely than in the placebo group, in which RRT was probably implemented earlier. Therefore, subclinical pulmonary impairment and potential volume overload have shifted the balance towards respiratory failure and adverse outcomes for the most vulnerable patients with ACLF grade 3. In summary, patients with ACLF grade 3 may need a more stringent indication for terlipressin, careful volume management, early pulmonary evaluation and, potentially, a more specific indication for RRT. The message of this study is a note of caution!