Noradrenaline in the treatment of patients with hepatorenal syndrome – Back to the roots?
Authors: Kurt Lenz
Journal: Journal of Hepatology (2012)

Noradrenaline vs. terlipressin in the treatment of hepatorenal syndrome: A randomized studyJournal of HepatologyVol. 56Issue 6PreviewVarious vasoconstrictors are useful in the management of hepatorenal syndrome (HRS). Terlipressin is the drug of choice; however, it is expensive. In this study, we evaluated safety and efficacy of terlipressin and noradrenaline in the treatment of HRS. Full-Text PDF Reply to: “Noradrenaline in the treatment of patients with hepatorenal syndrome – Back to the roots?”Journal of HepatologyVol. 57Issue 4PreviewWe thank Dr. Lenz for his interest in our paper. We agree with his view on noradrenaline and terlipressin therapy in hepatorenal syndrome (HRS). It would have been ideal to compare the two vasopressors if given as infusion and dose monitored by mean arterial pressure. However, terlipressin has been used as bolus therapy in most of the studies [1]. Gerbes et al. [2] treated 32 consecutive patients with HRS with continuous terlipressin infusion and reported reversal of HRS in 42% of patients in a retrospective study. Full-Text PDF Open Access In a randomized study, Singh et al. evaluated the efficacy of noradrenaline vs. terlipressin in the treatment of patients with HRS1 [[1]Singh V. Ghosh S. Singh B. Kumar P. Sharma N. Bhalla A. Noradrenaline vs. terlipressin in the treatment of hepatorenal syndrome: a randomized study.J Hepatol. 2012; 56: 1293-1298Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar]. According to their results, they suggest that noradrenaline is as safe and effective as terlipressin, but less expensive. The response of noradrenaline is mostly due to its vasoconstricting α-mimetic and perhaps additional ß-mimetic effects. The first report on a vasopressor therapy in a patient with renal dysfunction was published fifty years ago [[2]Gornel D.L. Lancestremere R.G. Papper S. Lowenstein L.M. Acute changes in renal excretion of water and solute in patients with laennecs cirrhosis, induced by the administration of the pressor amine metaraminol.J Clin Invest. 1962; 41: 594-603Crossref PubMed Scopus (36) Google Scholar]. Metaraminol, an α- and ß-mimetic substance, increased the excretion of water, sodium, and potassium, as well as the inulin and PAH clearance in cirrhotic patients with and without renal insufficiency. The following studies showed conflicting results [[3]Gutman R.A. Forrey A.W. Fleet W.P. Culter R.E. Vasopressor-induced natriuresis and altered intrarenal haemodynamics in cirrhotic man.Clin Sci Mol Med. 1973; 45: 19-34Google Scholar] and vasopressors have not been used since the late 1980s. Vasopressor therapy at that time was started with vasopressin derivates like ornipressin and later terlipressin. The idea of using ornipressin came from the fact that noradrenaline was not available any more in the mid 1980s. Recently, in placebo controlled studies with terlipressin and albumin, an increase in renal function in patients with HRS compared to albumin alone could be observed in about 40% of the patients. This combination is now recommended for the treatment of patients with HRS [[4]EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis.J Hepatol. 2010; 53: 397-417Abstract Full Text Full Text PDF PubMed Scopus (1377) Google Scholar]. In the last years, pilot studies using again noradrenaline showed an increase in renal function of patients with HRS. In a randomized study, Singh et al. found that noradrenaline was as effective as the “standard therapy” terlipressin. Has the time come to switch from terlipressin to noradrenaline? Arguments for using noradrenaline are costs, and the positive inotropic effect of noradrenaline, since cardiac insufficiency may be one cause of deteriorating renal function in cirrhosis [5Ruiz-del-Arbol L. Monescillo A. Arocena C. Valer P. Gines P. Moreira V. et al.Circulatory function and hepatorenal syndrome in cirrhosis.Hepatology. 2005; 42: 439-447Crossref PubMed Scopus (495) Google Scholar, 6Krag A. Bendtsen F.l. Henriksen J.H. Moller S. Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.Gut. 2010; 59: 105-110Crossref PubMed Scopus (286) Google Scholar]. Toward the use of noradrenaline is the necessity of a central venous catheter for noradrenaline infusion, because of the problem of bolus injection if using a peripheral venous catheter. On the other hand, one of the factors leading to renal hypoperfusion in advanced portal decompensation is loss of renal autoregulation [[7]Moore K. The hepatorenal syndrome.Clin Sci. 1997; 92: 433-443Crossref PubMed Scopus (53) Google Scholar]. In experimental data, a resetting of autoregulation could be induced by vasopressin [[8]Kirchheim H.R. Ehmke H. Vasoactive hormones: modulators of renal function.Clin Invest. 1994; 72: 685-687Crossref PubMed Scopus (4) Google Scholar], therefore terlipressin should be favoured. The relevance of the loss of autoregulation has been shown in many studies; as well as in the study of Singh et al., as mean arterial pressure was associated with response. Therefore, therapy should be primarily guided by the effect on arterial pressure, which was only done in this study, in the noradrenaline treated patients, but not in the terlipressin treated patients. Further studies comparing these substances should therefore use blood pressure for guiding the doses of the vasopressors used, as well as with terlipressin. This could be problematic in the case of bolus injections of terlipressin. Terlipressin has been shown, in a small retrospective study [[9]Gerbes A.L. Huber E. Gülberg V. Terlipressin for hepatorenal syndrome: continuous infusion as an alternative to iv bolus administration.Gastroenterology. 2009; 137: 1179Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar] and a pilot study [[10]Angeli P. Fasolato S. Cavallin M. Trotta E. Maresio G. Callegaro A. et al.Terlipressin given as continuous intravenous infusion versus terlipressin given as intravenous boluses in the treatment of type 1 hepatorenal syndrome (HRS1) in patients with cirrhosis.J Hepatol. 2009; 50: S73Abstract Full Text PDF Google Scholar], to be as effective when given as continuous infusion; a comparison of continuous infusion of terlipressin with noradrenaline, in a dose guided by mean arterial pressure, may be a better way to give a correct answer for a difference in the effectiveness of these two vasopressors. At least there are two points making the interpretation of the results presented by Singh et al. difficult: urine sodium concentration (60.6 ± 22.3 mval/L in patients with terlipressin and 46.9 ± 23.5 mval/L in patients with noradrenaline) was relatively high in patients with HRS. Sepsis was the main cause of short term mortality (14/29), therefore ongoing infection cannot be excluded in some of the patients at the start of vasopressing agents treatment. Unresolved infections would have had a major influence on changes in renal function and prognosis. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.