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Medwave 2015 Ago;15(Suppl 2):e6235 doi: 10.5867/medwave.2015.6235

�Noradrenalina o terlipresina para el s�ndrome hepatorrenal?

Noradrenaline or terlipressin for hepatorenal syndrome?

Pilar Celis, Gabriel Rada

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Abstract

Hepatorenal syndrome is a condition associated with very high mortality that may be reverted in some cases with vasoconstrictors. Terlipressin has generally been considered standard treatment, but noradrenaline has been postulated as alternative. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified six systematic reviews including four pertinent randomized controlled trials. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded noradrenaline and terlipressin probably have similar effects on reverting hepatorrenal syndrome and decreasing mortality, but noradrenaline is associated with less adverse effects, and has lower costs.

Problem

Hepatorenal syndrome is a condition associated with very high mortality. It is caused by intense renal vasoconstriction consequence of systemic and portal hemodynamic disturbances, particularly splacnic system vasodilation. Intravascular volume expansion and prolonged treatment with vasoconstrictors can revert kidney failure in some patients. Terlipressin improves renal function and decreases mortality, however it has frequent adverse effects, high cost, and it is not widely available. The use of alternative vasoconstrictors has been proposed, such as noradrenaline, which is widely available and has a lower cost.

Methods

We used Epistemonikos database, which is maintained by screening more than 30 databases, to identify systematic reviews and their included primary studies. With this information, we generated a structured summary using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analysis of the total of studies, a summary of findings table following the GRADE approach and a table of other considerations for decision-making.

Key messages

Noradrenaline and terlipressin probably have similar effects on reverting hepatorenal syndrome and decreasing mortality.
Noradrenaline is associated with less adverse effects than terlipressin.
Noradrenaline probably has a more favorable risk/benefit and cost/benefit ratio.

About the body of evidence for this question

What is the evidence.
See evidence matrix in Epistemonikos later

We found six systematic reviews [1],[2],[3],[4],[5],[6] including four randomized controlled trials, reported in five references [7],[8],[9],[10],[11].

What types of patients were included

The studies included adults with advanced liver disease (Child Pugh C). One study [8] included patients with type 2 hepatorenal syndrome, one did not limit by hepatorenal type [7] and two studies included type 1 hepatorenal syndrome [9],[11].

MELD score ranged between 20 and 30 points in three studies [7],[9],[11] and more than 30 in one [8].
Average creatinine level ranged between 2 and 3 mg/dl in all of the studies.

What types of interventions were included

All studies compared terlipressin to noradrenaline.
Noradrenaline dose ranged from 0.5 to 3 mg/hr. Terlipressin dose was 0.5 to 2 mg every 6 hours in three studies [8],[9],[11] and 1 to 2 mg every 4 hours in one [7].

What types of outcomes
were measured

Mortality, renal function recovery and adverse events.

Summary of findings

The information on the effects of noradrenaline compared to terlipressin is based on four randomized trials including 154 patients. All studies reported the outcomes: mortality, hepatorenal syndrome reversal and adverse effects.

Noradrenaline and terlipressin probably have similar effects on reverting hepatorenal syndrome. The certainty of the evidence is moderate.
Noradrenaline and terlipressin probably have similar effects on decreasing mortality in hepatorenal syndrome. The certainty of the evidence is moderate.
Noradrenaline is associated with less adverse effects than terlipressin. The certainty of the evidence is high.

Other considerations for decision-making

To whom this evidence does and does not apply

Included studies evaluated patients with advanced cirrhosis with high Meld or Child-Pugh scores, with type 1 or 2 hepatorenal syndrome, so this evidence can be applied to the majority of patients presenting with this condition.

About the outcomes included in this summary

The outcomes included are those considered critical for decision-making by the authors of this summary: mortality, hepatorenal syndrome reversal and adverse effects. These coincide with those mentioned in the main guidelines [12],[13].

Balance between benefits and risks, and certainty of the evidence

Existing evidence shows equivalent benefit, but less adverse effects, so probably the benefit/risk ratio is favorable to noradrenaline.
However, it is important to mention the difference in adverse effects is not given by severe adverse effects, which are similar for both terlipressin and noradrenaline, but mainly by the higher frequency of abdominal pain and an increase in stool frequency.

What would patients and their doctors think about this intervention

Terlipressin is considered standard treatment for hepatorenal syndrome, and consequently the main guidelines recommended it. Despite the existing evidence favoring noradrenaline there should be resistance from clinicians to adopt this therapy, at least while guidelines do not recommend it explicitly.

Resource considerations

Noradrenaline has lower cost, so if we consider there is no difference in efficacy, it is probably a cost-effective intervention.

Differences between this summary and other sources

The conclusions of this summary are in agreement with the more recent systematic review that includes all of the studies identified [4].
The main guidelines differ in their recommendations. The European guideline recommends terlipressin as first line therapy, but mentions noradrenaline as an alternative [12],[13]. The American guideline recommends using vasoactive agents, mainly octeotride or midodrine (terlipressin is not available in the United States), but recognizes the role of noradrenaline, limiting its use to critical care units.

Could this evidence change in the future?

The probability of future evidence changing the conclusion of this summary is low, because of the certainty of the evidence.
There are no other completed or ongoing studies evaluating this question, at least according to the International Controlled Trials Registry Platform of World Health Organization.

How we conducted this summary

Using automated and collaborative means, we compiled all the relevant evidence for the question of interest and we present it as a matrix of evidence.

Matrix of evidence (static version).

Follow the link to access the interactive version: Terlipressin versus noradrenaline for hepatorenal syndrome

Notes

The upper portion of the matrix of evidence will display a warning of “new evidence” if new systematic reviews are published after the publication of this summary. Even though the project considers the periodical update of these summaries, users are invited to comment in Medwave or to contact the authors through email if they find new evidence and the summary should be updated earlier. After creating an account in Epistemonikos, users will be able to save the matrixes and to receive automated notifications any time new evidence potentially relevant for the question appears.

The details about the methods used to produce these summaries are described here http://dx.doi.org/10.5867/medwave.2014.06.5997.

Epistemonikos foundation is a non-for-profit organization aiming to bring information closer to health decision-makers with technology. Its main development is Epistemonikos database (www.epistemonikos.org).

These summaries follow a rigorous process of internal peer review.

Conflicts of interest
The authors do not have relevant interests to declare.

Licencia Creative Commons

Esta obra de Medwave est� bajo una licencia Creative Commons Atribuci�n-NoComercial 3.0 Unported. Esta licencia permite el uso, distribuci�n y reproducci�n del art�culo en cualquier medio, siempre y cuando se otorgue el cr�dito correspondiente al autor del art�culo y al medio en que se publica, en este caso, Medwave.

Edici�n Julio 2022

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