Which Patients with Heart Failure Should Get Loop Diuretics as a Continuous Infusion? (Part 1)

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Loop diuretic management in the setting of acute decompensated heart failure (ADHF) has vexed clinicians for decades, and many hoped the Diuretic Optimization Strategies Evaluation (DOSE) trial would shed light on at least two competing strategies: low-dose versus high-dose loop diuretics, and administration as intravenous (IV) boluses versus a continuous infusion. In brief, the DOSE trial used a 2-by-2 factorial design to randomize 308 patients with ADHF to low-dose or high-dose loop diuretic therapy administered as IV boluses or a continuous infusion.¹ The primary efficacy and safety endpoints of the study were patient-reported global assessment of symptoms and renal function, respectively. For the purposes of this blog, I’ll be focusing on the comparison between IV bolus and continuous infusion administration.

Before discussing the results of the study, a couple of methodological issues are worth highlighting. First, the study enrolled patients with ADHF regardless of ejection fraction (EF), resulting in the inclusion of patients with either reduced or preserved EF heart failure (the mean EF in the study was 35±18%). The study also enrolled a population that was heterogeneous in other ways (e.g., heart failure etiology, renal function, use of guideline-directed medical therapy). Secondly, the primary endpoints were measured at 72 hours, but clinicians had the option of adjusting therapy at 48 hours (e.g., increasing or decreasing the dose, converting to oral therapy, adding a thiazide diuretic) based on patient response.

In the comparison of IV bolus and continuous infusion administration, there were no differences in either of the primary endpoints. However, patients receiving therapy as an IV bolus were twice as likely to require a dose increase at 48 hours (21% versus 11%, p=0.01) and twice as likely to receive a thiazide diuretic during the 72-hour treatment period (16% versus 7%, p=0.02).^1,2 These potential confounders make it difficult to conclude that IV boluses and continuous infusions are similarly efficacious and safe, and at least one small study demonstrated that continuous infusions confer greater urine output and shorter length of stay compared to IV boluses.³

With all that said, do I believe that continuous infusions are “better” than IV boluses? Not really. However, I do believe there are some populations that may benefit from continuous infusion administration, such as the following:

• Patients requiring high doses of IV loop diuretic therapy, such as those with a suboptimal response to IV boluses of 160-200 mg, or those in whom administering 2.5-times the previous outpatient dose (i.e., the strategy supported by DOSE) would result in boluses exceeding 160-200 mg. The adverse effects of loop diuretics (particularly ototoxicity) are often related to the cumulative dose given within a short period of time, which can make high-dose boluses riskier in patients with a degree of diuretic resistance. Spreading doses out as a continuous infusion may ameliorate these adverse effects. In this regard, I suspect that much of the benefit commonly attributed to continuous infusion diuretics is simply a consequence of being able to safely administer more diuretic therapy than with IV boluses.
• Patients with preload-dependent conditions, such as heart failure with preserved EF, aortic stenosis, or right ventricular failure. In patients with heart failure with reduced EF, the flatness of their Frank-Starling curve means that aggressive diuresis does not usually produce detrimental reductions in preload. However, in patients with heart failure with preserved EF and other preload-dependent states, the rapid intravascular volume depletion produced by intermittent IV boluses may reduce effective preload to a degree that it compromises cardiac output.
• Patients with conditions that impair plasma refill rate, such as hypoalbuminemia or isolated collections of fluid (e.g., effusions). Once blood volume exceeds venous capacitance, fluid begins to accumulate in the interstitial space, leading to the signs and symptoms of volume overload (e.g., edema). As volume is depleted during diuresis, it gets replaced by fluid diffusing back into the intravascular space. However, the rate of plasma refill may be reduced in certain patients, such as those with low oncotic pressure due to hypoalbuminemia. Rapid intravascular volume depletion as a result of IV bolus therapy may therefore exceed the rate at which fluid can diffuse out of the interstitial space. In contrast, the more gradual diuresis produced by a continuous infusion may avoid these transient states of intravascular hypovolemia.
• Patients experiencing hypotension with bolus administration. Although the aforementioned conditions are some of the most common etiologies associated with hypotension following bolus administration, others may also exist. In some cases, an underlying etiology may be indeterminable.

In conclusion, the heterogeneity of the population enrolled in DOSE makes it difficult to identify which patient populations, if any, may benefit from administering loop diuretic therapy as a continuous infusion. Additionally, changes made at 48 hours may have masked a potential benefit by the time primary outcomes were measured at 72 hours. As a result, there may be certain patients who benefit from empiric use of a continuous infusion strategy, especially since it is at least no less effective or safe compared to IV bolus administration. Some suggest that there are also practical advantages to continuous infusion administration (e.g., patients receive 24 hours/day of therapy whereas prescribers may forget to administer an extra IV bolus), but I contend that there are a number of practical disadvantages to counteract this claim. More on that as well as pearls for using continuous infusions in Part 2 of this series.

Brent N. Reed, PharmD, BCPS-AQ Cardiology, FAHA Dr. Reed is an assistant professor in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy, and practices as a clinical pharmacy specialist in advanced heart failure at the University of Maryland Medical Center in Baltimore, MD. Follow him on Twitter @brentnreed

References

1. Felker GM, Lee KL, Bull DA, et al; NHLBI Heart Failure Clinical Research Network. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011 Mar 3;364(9):797-805.
2. Supplementary Appendix for: Felker GM, Lee KL, Bull DA, et al; NHLBI Heart Failure Clinical Research Network. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011 Mar 3;364(9):797-805. Available at http://www.nejm.org/action/showSupplements?doi=10.1056%2FNEJMoa1005419. Accessed 2016 Oct 1.
3. Thomson MR, Nappi JM, Dunn SP, et al. Continuous versus intermittent infusion of furosemide in acute decompensated heart failure. J Card Fail. 2010 Mar;16(3):188-93. doi: 10.1016/j.cardfail.2009.11.005. Epub 2010 Jan 6.

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