Editorial: terlipressin in patients with ACLF grade 3—too late? Authorsʼ reply

We want to thank Drs. Trebicka and Zarbock for their valuable comments regarding our paper on the increased incidence of respiratory failure with terlipressin use in patients with type 1 hepatorenal syndrome (HRS1), especially in patients with grade 3 acuteonchronic liver failure (ACLF) (i.e., 3 or more organ failures).1,2 Terlipressin has been available in Europe for the management of complications of cirrhosis for over 36 years.3,4 As a result, our European colleagues were not able to conduct large, randomised, placebocontrolled trials to precisely identify the increased incidence of respiratory failure with terlipressin use. In addition, the concept of ACLF was not defined until recently5; the inclusion of lung failure as part of ACLF organ failures has increased assessment for possible respiratory failure in terlipressin recipients. Finally, variceal bleeding was the indication for most patients who received terlipressin. These patients are usually less ill than those with HRS1, and tend not to have multiorgan failure; this could have accounted for the absence of reporting. More recently, the European Medicines Evaluation Agency's Safety Committee, following the publications of the results of the CONFIRM trial,6 issued an alert bringing to attention the increased risk of respiratory failure with terlipressin for the indication of HRS1.7 Hopefully, this alert from the regulatory agency will lead to appropriate caution with the use of terlipressin. We recommend that, before any patient with HRS is given terlipressin, careful evaluation be done to determine whether the patient is a suitable candidate for it.7 Patients need to be assessed for baseline respiratory compromise; patients with pretreatment peripheral oxygen saturation of less than 90% while on room air should not receive terlipressin.2 Patients who have at least 3 organ failures, as per the European Association for the Study of the LiverChronic Liver Failure Consortium,8 are at increased risk of developing respiratory failure. Assessment of terlipressin candidacy should include a limitation of use in patients who have pretreatment serum creatinine of >5 mg/ dL as their chances for reversal of HRS1 are low.9 Patients listed for liver transplantation with high priority (e.g., MELD ≥35) should undergo careful risk– benefit analysis prior to treatment, as respiratory failure may result in a patient becoming ineligible for transplant. We agree with Drs. Trebicka and Zarbock that treating patients with HRS1 and grade 3 ACLF with terlipressin is too late. However, we should not dismiss all of these patients. As noted by Dr. Reiberger in an elegant editorial,10 some patients with HRS1 and ACLF grade 3 do respond to terlipressin with a reduction in serum creatinine to <1.5 mg/dl. Although 90day survival compared to nonresponders may not improve with treatment, the improvement in renal function may allow the few patients with a potentially reversible acute trigger for HRS1 (e.g,. alcoholic hepatitis or a flare of viral hepatitis) sufficient time to recover or to await liver transplant.