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Noradrenaline a cost-effective option for type 1 hepatorenal syndrome

Reuters Health • The Doctor's Channel Daily Newscast

NEW YORK (Reuters Health) – For reversal of type 1 hepatorenal syndrome, treatment with noradrenaline seems to work as well as terlipressin and is a lot less expensive, researchers from India report.

Hepatorenal syndrome, or HRS, is a form of renal failure seen in patients with end-stage liver disease. Splanchnic and systemic vasodilation together with intense renal vasoconstriction is the pathophysiologic hallmark of HRS. Vasoactive drugs are often used to treat the condition, which has a high mortality rate.

“Terlipressin is a drug of choice particularly in type 1 HRS,” Dr. Virendra Singh and colleagues from the Postgraduate Institute of Medical Education and Research in Chandigarh note in a report online February 7 in the Journal of Hepatology.

But terlipressin is expensive and not readily available in several countries, including the United States and Canada. Noradrenaline, in contrast, is widely available, relatively inexpensive and two recent studies reported reversal of HRS with this vasopressor.

Dr. Singh’s team evaluated the safety, efficacy and cost of terlipressin and noradrenaline in 46 patients with cirrhosis and type 1 HRS. All patients were admitted to the hospital for 15 days and followed up until 30 days.

All patients received albumin (20 grams/d). In addition, half of them received terlipressin as an intravenous bolus 0.5 mg every six hours. If this did not produce a significant reduction in serum creatinine level of 1 mg/dL or more over three days, the dose of terlipressin was increased in a stepwise fashion every three days to a maximum of 2 mg every six hours.

The other half received a continuous infusion of noradrenaline at a starting dose of 0.5 mg/hour with the goal of achieving an increase in mean arterial pressure of at least 10 mmHg or an increase in four-hour urine output of more than 200 mL. When one of these goals was not achieved, the noradrenaline dose was increased every four hours in steps of 0.5 mg/hour, up to a maximum of 3 mg/hour.

The researchers found no significant between-group difference in the rate of reversal of HRS – achieved in 9 of 23 terlipressin-treated patients (39.1%) and 10 of 23 (43.4%) noradrenaline-treated patients (p=0.764).

The investigators say the response rate seen in the study mirrors that seen in previous studies including a recent meta-analysis that showed reversal of type 1 HRS in 34% to 55% of patients.

Their results, they say, also confirm previous observations indicating that response to treatment leads to an improvement of circulatory function as evidenced by significant increases in urine output, urinary sodium, marked suppression of renin-angiotensin-aldosterone system and a trend towards increase in mean arterial pressure in responders at 15 days.

None of the patients who responded to treatment relapsed during follow-up. All patients who failed to respond to treatment died within 30 days of follow-up. The main causes of death were sepsis, liver failure, acute tubular necrosis with metabolic acidosis, GI hemorrhage and multiorgan failure.

In multivariate analysis, only the baseline Child Turcotte Pugh (CTP) score was a predictor of response to treatment with either agent.

The adverse effect profile in both the groups was similar “with no major side effect or
drug withdrawal or modification of doses,” the authors report. They note, however, that “most other studies” have found frequent side effects with use of terlipressin, including cardiovascular or ischemic complications, which have been reported in 10% to 15% of patients treated, on average, and usually requiring drug modification.

In the current study, four patients in the terlipressin group developed abdominal cramps and increased frequency of stools, one developed toe cyanosis and another developed transient ventricular extrasystole. These adverse events were self-limiting.

In the noradrenaline group, two patients experienced atypical chest pain with normal electrocardiogram, troponin and creatine phosphokinase (CPK). No adverse effects related to the intravenous albumin infusion were seen.

A cost-effectiveness analysis showed a “major advantage” to noradrenaline over terlipressin. The cost of treatment for 15 days was 945 euros for terlipressin vs 275 euros for noradrenaline (p<0.05), not including the cost of albumin or hospital expenses.

The investigators say more studies are needed to establish noradrenaline as an alternate therapy. The authors did not respond to a request made by Reuters Health for comment.


Journal of Hepatology 2012