Monday, June 4, 2012

Innovation or impersonation: low-dose dopamine in heart failure

Although renal dysfunction is commonly associated with the use of aggressive diuretic therapy in patients with acute decompensated heart failure (ADHF), strategies for preventing or overcoming this phenomenon remain a considerable challenge.  Low-dose dopamine has been proposed as a novel approach for promoting diuresis in patients with ADHF, but its use in this setting remains controversial. Enthusiasm for this strategy was renewed when preliminary results from the DAD-HF trial were announced in early 2010; however, when full details of the trial became available later that year [1], many clinicians felt that the trial's limitations outweighed many of its proposed benefits.

In DAD-HF, 60 patients with ADHF of New York Heart Association (NYHA) Class IV severity were randomized to one of two treatment arms: (1) a high-dose furosemide infusion (20 mg/hour), or (2) a low-dose furosemide infusion (5 mg/hour) plus dopamine infusion (5 mcg/kg/min).  Patients with severe renal impairment (GFR < 30 mL/min) were excluded. Prior to being allocated to one of the two treatment arms, all patients received a 40-mg intravenous bolus of furosemide. All study infusions were discontinued after a total of 8 hours and further management was left to the discretion of the attending physician.

No differences in total urine output (UOP) or dyspnea symptoms were observed at 8 hours. Significant differences in the incidence of worsening renal function (defined as > 0.3 mg/dL rise in serum creatinine at 24 hours) were observed in the high-dose furosemide group (30%, compared to 6.7% in the low-dose furosemide plus dopamine group, p = 0.042); however, a difference was not observed when a second definition for worsening renal function was used (> 20% decrease in GFR at 24 hours). When patients were observed for the duration of hospitalization, results were reversed; no differences were observed when the change in serum creatinine was used to define renal dysfunction, whereas a greater percentage of patients in the high-dose furosemide group had worsening renal function when GFR was used (69.2% versus 34.6%, p = 0.025).  No differences in length of stay, readmission rate, or mortality were observed.

Although the results of DAD-HF are not exactly compelling, the authors go on to make several bold statements about the proposed renoprotective benefits of dopamine. However, the limitations of this trial do warrant further discussion, as I believe they significantly influence how the results should be interpreted and applied to clinical practice.
  • The trial was small (n = 60) and included a considerably homogenous patient population. The hemodynamic effects of dopamine in ADHF are a function of disease severity [2], so it is unknown how patients of other NYHA classes would respond to this management strategy;
  • The study protocol only ran for a total of 8 hours. Given the pharmacokinetics of intravenous furosemide, a significant portion of the clinical response at 8 hours (i.e., when urine output was recorded) can attributed to the initial intravenous bolus dose (which was administered to all patients), and perhaps the first several hours of the continuous furosemide infusion. Given the impaired clearance in patients with ADHF, it is unlikely that many patients were at steady state when the infusions were discontinued and the 8-hour assessment of urine output was performed. 
  • Assessments of efficacy were performed after 8 hours while assessments of safety were made after 24 hours (and throughout the course of hospitalization). However, no information was provided on how patients were managed after their 8-hour protocols were completed (left to the discretion of the attending physician), which could have influenced these results.
  • The investigators did not include a low-dose furosemide only group (i.e., no dopamine), so it is unknown whether the differences observed in DAD-HF can be attributed to dopamine per se, or the lower dose of furosemide used in this group. As the authors note in their discussion, the results of the DOSE trial demonstrated that higher doses of furosemide (whether administered as an intermittent intravenous bolus or continuous infusion) are clearly associated with worsening renal function in patients with ADHF [3]. The authors attempt to discount the possibility that their findings was due to lower doses of furosemide alone by claiming that the addition of dopamine provided a comparable degree of diuresis as high-dose furosemide but without the subsequent worsening of renal function. However, as described above, assessments of efficacy in DAD-HF were performed at 8 hours (versus 72 hours in DOSE), so this hardly seems like a fair comparison.
  • The dose of dopamine (5 mcg/kg/min) used in DAD-HF is hardly "low-dose" by any definition.  In previous studies, the doses of dopamine thought to confer renoprotection are < 2 mcg/kg/min, where activation of renal dopaminergic receptors predominate. However, at doses of 3-5 mcg/kg/min, dopamine is known to exert positive inotropic effects, where improvements in renal blood flow can also be attributed to improved cardiac output.  Even in the studies cited by the authors, the doses at which dopamine improved renal hemodynamics were also those at which cardiac index was highest [2].  In other words, it cannot be said from the present study that dopamine at 5 mcg/kg/min offers any greater degree of renoprotection than if a traditional inotrope (e.g., dobutamine, milrinone) had been used.
  • Finally, only surrogate markers (e.g., serum creatinine, GFR calculations) were used to determine changes in renal function. While these markers are certainly the most practical to measure and have been correlated with clinical endpoints in other investigations, it seems difficult to justify their use in some of the bold statements made by the authors of DAD-HF.  No comments are made on more clinically relevant measures of renal dysfunction (e.g., time to continuous renal replacement therapy [CRRT]), or whether changes in serum creatinine or GFR were still present at 30 or 60 days after randomization. While the authors present an excellent review on the pharmacologic effects of dopamine, if these effects do not translate into meaningful improvements in clinical outcomes, what difference dose it make?
Therefore, based on the limitations highlighted above (and no additional evidence to the contrary), I tend to recommend against using dopamine as a strategy for preventing or ameliorating the renal dysfunction associated with aggressive diuretic therapy. While the adverse effects of dopamine at doses of < 5 mcg/kg/min are arguably low, I do believe it often delays initiation of more appropriate management strategies when necessary (i.e., inotropes, CRRT) while we wait to see if it will work.  That being said, I am not entirely opposed to the use of dopamine in patients with ADHF, as there are some scenarios where it has its advantages:
  • Patients with mixed cardiogenic/septic shock or in whom the primary contributor to shock is unknown;
  • Patients who require inotrope therapy but have labile or tenuous blood pressures and in whom central hemodynamic parameters are unknown (i.e., scenarios in which dobutamine or milrinone may be a riskier choice); in this situation, dopamine may serve as a temporary measure until blood pressures improve (or a pulmonary artery catheter can be placed), or as a bridge to initiating a traditional inotrope;
  • Patients whose hemodynamics are especially sensitive to changes in intravascular fluid volume, such as those associated with aggressive diuresis or intermittent hemodialysis.
Otherwise, I am not sure that DAD-HF contributes much to our knowledge on the management of patients with ADHF or how we might avoid renal injury in the context of aggressive diuretic therapy.  Additionally, based on the reasons outlined above, I am not sure it is an appropriate strategy to attempt in patients with ADHF simply because we do not yet have a more proven alternative.

For a discussion on the myths of low-dose dopamine in critically ill patients with renal dysfunction (i.e., in the absence of ADHF), please see this post.

  1. Giamouzis G, Butler J, Triposkiadis F, et al. Impact of dopamine infusion on renal function in hospitalized heart failure patients: results of the Dopamine in Acute Decompensated Heart Failure (DAD-HF) Trial. J Card Fail. 2010 Dec;16(12):922-30.
  2. Ungar A, Fumagalli S, Marchionni N, et al. Renal, but not systemic, hemodynamic effects of dopamine are influenced by the severity of congestive heart failure. Crit Care Med. 2004 May;32(5):1125-9.
  3. Felker GM, Lee KL, O'Connor CM, et al; for the 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.

1 comment:

Anonymous said...

It is also interesting to note that at 24 hours, the only between-group difference seen in renal markers was a lower serum potassium in the HDF group, which is an expected consequence of high-dose furosemide (i.e., while the HDF group had increased serum creatinine over baseline at 24 hours, this serum creatinine was not significantly higher than that seen in the LDFD group at 24 hours)