Noradrenalin vs terlipressin in patients with hepatorenal syndrome: A prospective, randomized, unblinded, pilot study☆,☆☆
Introduction
Hepatorenal syndrome (HRS) is a major complication of cirrhosis. It is characterized by marked arterial vasodilation (mainly of the splanchnic vessels), in sharp contrast with a severe renal vasoconstriction [1]. Arterial dilation is a key pathogenic event of HRS, leading to reduction of the effective blood volume, homeostatic activation of vasoactive systems and renal vasoconstriction with decrease in renal blood flow [1], [2], [3], [4]. The clinical signs of HRS vary depending on the clinical pattern. HRS type 1 is characterized by rapidly progressive renal failure and a very poor short term prognosis, with a median survival of only about 2 weeks; HRS type 2 by a moderate and more stable renal failure, with a median survival of about 6 months [1], [2]. The management of HRS still constitutes a major challenge. Liver transplantation is the ideal treatment [5], but it has important inherent drawbacks, such as organ shortage and the time needed to perform the transplant, often too long to allow the survival of these patients. The management of HRS has focused on improving renal function, thus extending patients’ survival and allowing the performance of the liver transplant. In recent years, remarkable results have been obtained using vasoconstrictor drugs. By improving the effective blood volume, vasoconstrictors induce the suppression of homeostatic vasoactive systems and increase renal blood flow and glomerular filtration rate [6], [7], [8], [9], [10], [11]. Furthermore, it has been suggested that the efficacy of this therapy is further improved by the use of albumin [12]. Among vasoconstrictors, terlipressin, a V1 vasopressin agonist, has currently the best efficacy pedigree [8], [9], [10], [11], [12]. However, it is expensive and is not available in many countries, including North America. More recently, it was suggested that alpha-adrenergic drugs such as noradrenalin [13] and midodrine [14], [15] may be also effective in HRS. Noradrenalin would have the potential advantage of wider availability and of lower costs. The current prospective, randomized, unblinded, pilot study was undertaken to assess the efficacy and safety of noradrenalin vs terlipressin in patients with HRS.
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Patients
This prospective study was conducted in the gastroenterology and hepatology unit of our hospital. Thirty-six consecutive patients presenting with features of cirrhosis and renal failure consistent with HRS were investigated for inclusion. The diagnosis of cirrhosis was based on clinical, laboratory and ultrasonographic findings. HRS was diagnosed by using the criteria of the International Ascites Club [1]. Patients with heart or respiratory failure, coronary disease and peripheral artery
Patient characteristics
There were no significant differences between the two groups with respect to demographic, clinical and laboratory baseline characteristics (Table 1).
Response to therapy
Seven of the 10 patients (70%) treated with noradrenalin plus albumin and 10 of the 12 patients (83%) treated with terlipressin plus albumin showed a complete response to therapy (p = ns); the remaining five patients showed no response to therapy. In patients showing reversal of HRS, serum creatinine decreased from 2.3 ± 0.2 mg/dL (range 3.1–1.8 mg/dL)
Discussion
The results of this study suggest that in patients with HRS treatment with noradrenalin and albumin is as effective as terlipressin and albumin. Noradrenalin led to HRS reversal in 70% of the patients, a percentage similar to the rate obtained with terlipressin (83%) and in agreement with the only study published so far on the use of noradrenalin in patients with HRS [13]. The response rate was high with either treatments both in type 1 and in type 2 HRS. The latter data represent the first
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The authors who have taken part in this study declared that they have no relationship with the manufacturers of the drugs involved either in the past or present and did not receive funding from the manufacturers to carry out their research. The authors did not receive funding from any source to carry out their study.
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Our clinical trial is registered in the International Trial Registry of the US National Institute of Health (see www.clinicaltrial.gov). The ClinicalTrial.gov identifier is: NCT00370253.