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Medwave 2016;16(suppl 2):e6426 doi: 10.5867/medwave.2016.6426

�Diur�ticos de asa en infusi�n continua o en bolo en la insuficiencia cardiaca congestiva?

Continuous infusion or bolus injection of loop diuretics for congestive heart failure?

Patricio Zepeda, Carmen Rain, Paola Sep�lveda

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Abstract

Loop diuretics are widely used in acute heart failure. However, there is controversy about the superiority of continuous infusion over bolus administration. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified four systematic reviews including 11 pertinent randomized controlled trials overall. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded continuous administration of loop diuretics probably reduces mortality and length of stay compared to intermittent administration in patients with acute heart failure.

Problem

The management of patients with acute heart failure is largely based on the use of loop diuretics. However, they may be administered as intermittent bolus or continuous infusion.

While bolus administration of furosemide is associated with lower costs, it could increase adverse effects as a consequence of changes in volume which would increase plasma concentration of the drug. Moreover, high doses administered intermittently may produce acute tolerance to diuretics by compensatory renal retention after their effect has subsided. Continuous administration of furosemide has been proposed as a solution to these problems but there is controversy about the clinical effects of both approaches.

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

Continuous administration of loop diuretics probably reduces mortality and length of stay compared to intermittent administration in patients with acute heart failure.
Risk/benefit and cost/benefit probably favor continuous administration.

About the body of evidence for this question

What is the evidence. See evidence matrix in Epistemonikos later	We found four systematic reviews [1],[2],[3],[4], including 11 randomized controlled trials reported in 12 articles [5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16].
What types of patients were included	All studies included adults with acute heart failure with an average age ranging from 53 to 74 years. Four studies included patients with functional capacity between III and IV [8],[11],[15], two studies included patients with functional capacity between II and III [5],[10] while the remaining studies did not describe functional capacity. Regarding renal function, all studies included patients with creatinine ≤2 mg/dL.
What types of interventions were included	Regarding continuous infusion of loop diuretics, one study used torsemide [10] and the remaining ten used furosemide; of these, four [7],[11],[14],[15] used a loading dose of 40 mg followed by continuous infusion at variable rate. One study did not report doses and only reported it was determined by the attending physician. All studies compared against bolus injection. Two studies [8],[10] administered bolus injection once a day, seven [5],[6],[7],[9],[11],[14],[15] twice a day and one used three boluses per day. Daily doses of furosemide ranged from 120 mg/day to 2000 mg/day in the continuous infusion group and from 90 mg/day to 2000 mg/day in the bolus injection group.
What types of outcomes were measured	All-cause mortality, cardiac death, length of stay, electrolyte disturbances, changes in serum creatinine, adverse effects (hair loss and tinnitus), body weight, urine output, and urinary sodium excretion.

We found three systematic reviews [5], [6], [7], including 14 studies reported in 21 references [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28]. Eight studies correspond to randomized controlled trials (15 references [9], [10], [11], [12], [13], [14], [16], [17], [19], [21], [22], [23], [24], [26], [27]). This table and the summary in general are based on the latter. One study [15] did not contribute data to any of the outcomes of interest.

Summary of findings

Information on the effects of continuous loop diuretics compared to bolus injection for congestive heart failure is based on 11 randomized trials including 622 patients. Four studies reported overall mortality and four studies reported length of stay.

Continuous administration of loop diuretics probably reduces mortality compared to intermittent administration in patients with acute heart failure. The certainty of the evidence is moderate.
Continuous administration of loop diuretics probably reduces length of stay compared to intermittent administration in patients with acute heart failure. The certainty of the evidence is moderate.

Other considerations for decision-making

To whom this evidence does and does not apply

The information in this summary applies to adult patients with decompensated acute heart failure from any cause, with renal function close to normality (serum creatinine ≤2 mg/dL)

It is important to note in clinical practice is frequent to use larger boluses of loop diuretics than described in most studies.

About the outcomes included in this summary

The outcomes presented are those considered critical for decision making in the opinion of the authors of the summary and coincide with those reported by the systematic reviews identified [1],[2],[3],[4].

Balance between benefits and risks, and certainty of the evidence

Continuous infusion of furosemide confers a benefit on mortality and length of stay with moderate certainty. While there is a greater degree of uncertainty concerning some outcomes as hypokalemia and hypomagnesemia (RR 0.78 [95% CI 0.39 to 1.56], very low certainty of the evidence) or increase in serum creatinine (MD -0.45 [95% CI -0.42 to -0.47]), these outcomes are relatively less important than the former, so the balance is clearly in favor of using continuous infusion.

Resource considerations

The total amount of diuretics used in both groups of the studies analyzed was similar.

Since it is a relatively low-cost intervention, and has an impact on mortality and length of stay, it would be a cost/effective intervention.

In relation to the direct cost, while some cost items may vary between the two options (cost of the pump and staff needed to use it in continuous infusion; cost of fluids and personnel to administer the bolus for intermittent injection), probably these differences are of little relevance for decision-making. Moreover, there may be savings from reduced length of stay and extra costs resulting from adverse effects.

Differences between this summary and other sources

The systematic reviews identified disagree in their conclusions regarding the effect on mortality and length of stay. Our summary is consistent with one of them [3], while the other two [1],[2] conclude there are no differences.

Two of the three main clinical guidelines on this topic [17],[18],[19],[20] address the question of this summary, presenting recommendations discordant with our findings. One [19] mentions it is not clear what is the optimal form of administration, and there might be no difference between both alternatives. While in the other guideline [20] both forms of administration are recommended indistinctly.

Could this evidence change in the future?

The likelihood of future evidence changing the conclusions of this summary is low due to the certainty of the evidence.

We did not identify ongoing studies that may increase the certainty of this evidence in the future.

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.

Follow the link to access the interactive version Continuous infusion versus bolus injection
of loop diuretics for heart failure

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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