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Author: Brent N. Reed, PharmD, BCPS-AQ Cardiology, FAHA

Of the available agents for treating shock, dopamine remains unusually popular. The conventional teaching is that dopamine exerts its effects in a dose-dependent fashion – low doses (<3 mcg/kg/min) affect primarily dopaminergic receptors in the kidney (improving renal blood flow), medium doses (3-10 mcg/kg/min) affect beta-adrenergic receptors in the myocardium (increasing inotropy and chronotropy), and high doses (> 10 mcg/kg/min) affect alpha-adrenergic receptors in vascular smooth muscle (exerting a vasopressor effect). Although these varying effects are thought to afford it several advantages compared to other vasoactive agents, below I’ll share three reasons why you should consider replacing dopamine in your practice.


1. Renal-dose dopamine is a myth.
I could write an entire post on renal-dose dopamine, as it is truly a zombie of the clinical world – no matter how much data you throw at it, it just keeps coming back for more. Although intuitively it would seem like the activation of dopaminergic receptors at low doses would exert a renoprotective affect, renal-dose dopamine (or low-dose dopamine) has failed to produce clinically meaningful improvements in renal function in a number of clinical trials. Below is a very annotated bibliography:

  • In a randomized controlled trial of 328 critically ill patients, low-dose dopamine failed to improve urine output, markers of renal function, or any clinical endpoints (e.g., need for renal replacement therapy, mortality) (1).
  • In a large meta-analysis of 61 trials, low-dose dopamine conferred a transient but clinically insignificant improvement in urine output in the first 24 hours but not at any other time point; it also failed to improve other renal endpoints (2).
  • In the Dopamine in Acute Decompensated Heart Failure (DAD-HF) trial, 60 patients with acute decompensated heart failure (ADHF) were randomized to high-dose furosemide (20 mg/h) or low-dose furosemide (5 mg/h) plus low-dose dopamine (5 mcg/kg/min) (3). Less renal dysfunction was observed in the latter group but the results were limited by the lack of an arm in which patients received low-dose furosemide alone. A low-dose furosemide arm was included in the follow-up DAD-HF II trial, and indeed the differences in renal function were explained by diuretic dose and not the addition of dopamine (4). However, since the dose of dopamine used was 5 mcg/kg/min (i.e., not really “low-dose”), the door for renal-dose dopamine in ADHF remained open.
  • In the Renal Optimization Strategies Evaluation (ROSE) trial, 241 patients with ADHF and renal dysfunction were randomized to low-dose dopamine (2 mcg/kg/min) or placebo, and again low-dose dopamine failed to improve urine output or renal function (5). Notably it did increase the rate of tachycardia (i.e., a beta-adrenergic effect), demonstrating that its effects are not limited to dopaminergic receptors at doses as low as 2 mcg/kg/min. However, since the results appeared to differ by ejection fraction, the door remained open yet again.
  • In the Randomized Evaluation of Heart Failure With Preserved Ejection Fraction Patients With Acute Heart Failure and Dopamine (ROPA-DOP) trial, patients with ADHF and exclusively heart failure with preserved ejection fraction (HFpEF) were randomized to low-dose dopamine (3 mcg/kg/min) or diuretics alone (6). As it did in the trials above, low-dose dopamine again failed to improve urine output or markers of renal function.


2. Dopamine is a dirty drug.
Some see the varying effects of dopamine as an advantage in patients with shock of unclear etiology. I would counter that it only obscuresthe underlying etiology of hypotension and potentially delays the initiation of appropriate therapy (which may explain why it performs worse when compared to norepinephrine in patients with cardiogenic shock) (7).

The above dose ranges and their corresponding clinical effects are only rules of thumb, and ROSE clearly showed that beta-mediated effects are present even at low doses. I would imagine the same is true as dopamine is increased towards the “high-dose” range. Dopamine is typically titrated to achieve a target mean arterial pressure (MAP), but MAP is a complex hemodynamic parameter influenced by both cardiac output and systemic vascular resistance. If dopamine is titrated up and the MAP improves, is it because the patient is in cardiogenic shock and cardiac output improved as a result of dopamine’s effects on beta receptors? Or, is the patient in septic shock and MAP improved because dopamine’s effects on peripheral alpha receptors led to an increase in systemic vascular resistance? The point is, it is impossible to know in the absence of a pulmonary artery catheter, making dopamine incredibly difficult to use in mixed shock syndromes.

An alternative strategy in the above scenario would be to use a combination of a traditional inotrope, such as dobutamine, and a vasopressor with mostly vasoconstricting effects but consistent inotropic effects across the dosing range, such as norepinephrine. Each can be independently titrated to response, which can also help clarify the patient’s underlying shock etiology.


3. Safer alternatives exist.
The safety and efficacy of dopamine in the treatment of shock was compared to norepinephrine in the Sepsis Occurrence in Acutely Ill Patients (SOAP) II trial, in which 1679 patients with shock were randomized to one of the two agents as a first-line vasopressor (7). No differences were observed in the primary endpoint of death at 28 days (52.5% with dopamine vs. 48.5% with norepinephrine, p=0.10), but dopamine appeared to increase mortality among the subgroup of patients with cardiogenic shock. Perhaps the most important finding of SOAP II was that dopamine was associated with a twofold increase in the risk of arrhythmia (24.1% vs. 12.4% with norepinephrine, p < 0.001), a difference driven primarily by the rates of atrial fibrillation (20.5 vs. 11.0% with norepinephrine). Although atrial fibrillation is certainly less concerning than a ventricular arrhythmia, it still complicates the treatment of shock and portends an increased mortality risk (8).


OK, so when should I use dopamine?
Given the reasons above, there are few instances in which dopamine should be a preferred agent in shock. One niche in which I’ll still consider its use is as an alternative to isoproterenol in the initial treatment of severe and/or symptomatic bradycardia. Although the latter is usually my preferred agent for chronotropy, the incredibly high cost of isoproterenol has made it an agent of last resort.


Bottom Line
Dopamine is less safe than norepinephrine for the management of shock and it can obscure the etiology of hypotension in patients with mixed shock syndromes. Despite multiple attempts to demonstrate otherwise, at low doses it fails to exert a clinically meaningful benefit on renal function yet still increases the risk of arrhythmias.

 

Brent N. Reed, PharmD, BCPS-AQ Cardiology, FAHA

Dr. Reed is an associate 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 his website or on Twitter @brentnreed.

References

  1. Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet Lond. Engl. 2000;356:2139–2143.
  2. Friedrich JO, Adhikari N, Herridge MS, Beyene J. Meta-analysis: low-dose dopamine increases urine output but does not prevent renal dysfunction or death. Ann. Intern. Med. 2005;142:510–524.
  3. Giamouzis G, Butler J, Starling RC, 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;16:922–930.
  4. Triposkiadis FK, Butler J, Karayannis G, et al. Efficacy and safety of high dose versus low dose furosemide with or without dopamine infusion: the Dopamine in Acute Decompensated Heart Failure II (DAD-HF II) trial. Int. J. Cardiol. 2014;172:115–121.
  5. Chen HH, Anstrom KJ, Givertz MM, et al. Low-Dose Dopamine or Low-Dose Nesiritide in Acute Heart Failure With Renal Dysfunction: The ROSE Acute Heart Failure Randomized Trial. JAMA J. Am. Med. Assoc. 2013.
  6. Sharma K, Vaishnav J, Kalathiya R, et al. Randomized Evaluation of Heart Failure With Preserved Ejection Fraction Patients With Acute Heart Failure and Dopamine: The ROPA-DOP Trial. JACC Heart Fail. 2018.
  7. De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N. Engl. J. Med. 2010;362:779–789.
  8. Walkey AJ, Wiener RS, Ghobrial JM, Curtis LH, Benjamin EJ. Incident stroke and mortality associated with new-onset atrial fibrillation in patients hospitalized with severe sepsis. JAMA 2011;306:2248–2254.
3 Reasons You Should Stop Using Dopamine

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2 thoughts on “3 Reasons You Should Stop Using Dopamine

  • August 31, 2018 at 12:42 pm
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    Our cardiologists are still recommending this for symptomatic bradycardia, but with all the negative press I’ve been looking for an answer regarding cleaner, more appropriate agents. Assuming I have no access to isoproterenol, is there any evidence, chatter, practice patterns that you are aware of using other agents such as epi or norepi for severe, symptomatic bradycardia (besides pacing)?
    Great post and thank you.

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    • August 31, 2018 at 11:32 pm
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      Thanks for the kudos! I’m not aware of any data on practice patterns but our posting of this blog did seem to generate quite a bit of discussion on Twitter. I can’t think of any agents for symptomatic bradycardia that would be cleaner than dopamine (with the exception of isoproterenol, of course). Epinephrine would be a reasonable alternative, although I consider it to fairly dirty when used for this purpose, too — difficulty to get isolated chronotropy without also getting the inotropy and vasoconstriction that comes with it. I’ve heard of clinicians using norepinephrine for symptomatic bradycardia but I’ve just found that its vasoconstrictings effects tend to predominate clinically, requiring higher doses to elicit a heart rate response.

      Reply

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