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1 Lausanne, Switzerland
2 Kingston, Ontario
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Article appraised |
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 TOP Article appraised Commentary by D. BraccoReferencesCommentary by J. L....References |
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Structured abstract
Question: Does low-dose (< 5 µg•kg-1•min-1) dopamine prevent death, acute renal failure (ARF), or hemodialysis requirements in critically ill patients?
Data sources: Studies were identified by MEDLINE (1966–1999) search for articles on kidney (drug effects) and dopamine, limited to clinical trials and systematic reviews. Citation review of original reports and reviews was also performed.
Study selection: Studies were selected if they were studied human subjects, used low-dose (< 5 µg•kg-1•min-1) dopamine to prevent or treat ARF, and reported primary data on death, development or worsening of ARF, or hemodialysis requirement. The diagnosis of ARF required biochemical criteria ± oliguria; indication for hemodialysis required clinical criteria or use of any renal support at least once for a given patient. Biochemical and clinical criteria were not standardized.
Data extraction: Data were extracted on trial design, patient characteristics, mortality rates, incidence and severity of ARF, and use of hemodialysis. Meta-analysis was restricted to data from randomized clinical trials.
Main results: Seventeen trials with a total of 854 patients met the inclusion criteria. Low-dose dopamine did not change the frequency of death, onset of ARF, or hemodialysis requirements (Table
). Subgroup analyses did not show any statistical differences in outcomes in patients without exposure to radiocontrast dye or in patients with cardiac disease.
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Funding: Not reported.
Correespondence:Dr. John A. Kellum, University of Pittsburgh Medical Center, Division of Critical Care Medicine, 200 Lothrop Street, Pittsburgh, PA 15213-2582, USA. E-mail: kellumja{at}anes.upmc
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Commentary by D. Bracco |
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TOPArticle appraisedCommentary by D. BraccoReferencesCommentary by J. L....References |
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Physiologic basis of action of dopamine on the kidneys
At low concentrations, dopamine acts on DA adrenergic receptors in the kidney's vascular bed and tubule. Activation of these receptors leads to renal vasodilatation and inhibition of proximal sodium reabsorption. The increased renal blood flow and glomerular filtration rate results in diuresis and natriuresis. However, this observation has not been demonstrated clearly in critically ill patients.
The increased sodium load delivered in the distal tubule must be reabsorbed. Sodium reabsorption is energy consuming. Dopamine increases diuresis and natriuresis at the expense of increased oxygen demand (Figure). ATP depletion in the kidney during ARF has been demonstrated by magnetic resonance imaging.1
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In a hypoxic kidney, administration of a drug that potentially increases oxygen demand represents a risk. If renal vasodilatation is insufficient to overcome the increased oxygen demand, dopamine could worsen hypoxia and could lead subsequently to renal failure.
Low-dose dopamine (0.5–2 µg•kg-1•min-1) results in plasma levels 100 times greater than normal physiological levels. Plasma dopamine clearance is reduced in critically ill patients. The pharmacokinetics and pharmacodynamics of dopamine in the critically ill are difficult to predict. An indirect effect on cardiac output and blood pressure must be taken into account. Improvements in systemic hemodynamics may affect local and regional blood flow. The administration of low-dose dopamine is not harmless: it may increase cardiac output and oxygen demand and expose the patient to an increased risk of arrhythmia and myocardial ischemia. It interferes with the endocrine system (decreased prolactin, growth hormone, and thyrotropin), electrolyte balance (hypokaliemia and hypophosphatemia), metabolism (negative nitrogen balance), and the immunological system (decreased T-cell function).
Kellum and Decker's meta-analysis, which includes 17 studies on 854 patients, shows no improvement in extracorporeal support or mortality. These findings have been confirmed by two recent studies2,3 showing no difference in the evolution of renal failure, the need for extracorporeal support, and mortality. The Australasian study had detailed end points in which no beneficial effect of dopamine was demonstrated.2
The time has come to examine the evidence. There are no data from prospective, well-controlled, randomized clinical trials that support the use of dopamine in critically ill patients with ARF or at risk of ARF. "Physiological" data in volunteers with a large oxygen balance reserve cannot be extrapolated to critically ill patients where impaired renal oxygen balance is the fundamental mechanism leading to ARF.
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References |
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TOPArticle appraisedCommentary by D. BraccoReferencesCommentary by J. L....References |
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2 Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Lancet 2000; 356: 2139–43.[Medline]
3 Marik PE, Iglesias J, and the NORASEPT II Study Investigators. Low-dose dopamine does not prevent acute renal failure in patients with septic shock and oliguria. Am J Med 1999; 107: 387–90.[Medline]
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Commentary by J. L. Parlow |
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TOPArticle appraisedCommentary by D. BraccoReferencesCommentary by J. L....References |
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In the design of this study, the authors have satisfied most of the desirable criteria for a meta-analysis.2 MEDLINE and manual searching was done of 33 years of literature. Although it is arguable whether or not elective vascular and cardiac surgical patients fall into the category of "critically ill" patients, the included population encompasses a wide range of patients who are at increased risk of acute renal failure (ARF) and who commonly receive prophylactic dopamine infusion. The endpoints studied are clear and important, including death, requirement for hemodialysis, and development or worsening of ARF. An inherent limitation of meta-analysis is that the operational definitions of ARF and need for dialysis differed in the various trials – it seems only death could be defined to all investigators' satisfaction! Furthermore, sufficient power was attained for only two of the primary outcomes: development of ARF and need for hemodialysis.
The authors report that, despite traditional thinking, dopamine has no effect on the development of ARF. In their discussion, the authors boldly state that dopamine should not be used for the prevention or treatment of ARF and provide a rationale for this conclusion. Although dopamine increases renal blood flow, decreased renal blood flow does not necessarily result in ischemic ARF and increased renal blood flow does not necessarily prevent this injury. In fact, the authors refer to previous work suggesting that dopamine may worsen renal injury in certain situations, despite increasing renal blood flow, and that anti-dopaminergic agents are not associated with ARF although they block the renal vascular effects of dopamine.
From the clinical perspective, the mechanisms involved in perioperative ARF may be distinct from those involved in nonoperative critically ill patients. Of the 58 studies reviewed, 20 involved surgical patients; only nine of these reported outcomes studied in this meta-analysis. Patients undergoing vascular and cardiac surgery (totalling 256) comprised only four of the studies analyzed. Thus, there was insufficient power to analyze these patients as a subgroup. When one examines the results of the perioperative trials, there was not even a trend to suggest a beneficial effect with dopamine.
What can we conclude? Many etiological factors involved in perioperative ARF may be specific to the perioperative setting, including particular nephrotoxic agents, hypotension from hypovolemia, cardiopulmonary bypass, and abrupt hypoperfusion from aortic cross clamping;3 however, despite the low numbers of perioperative patients examined in this study, the authors provide as much physiological rationale against the use of dopamine as supporting it. Thus, based on the existing evidence, one can conclude that perioperative prophylactic dopamine is not better than placebo and that even the theoretical benefit of dopamine is uncertain. The authors conclude their paper with the recommendation that further study of the effects of dopamine should be undertaken only as large, well-powered randomized clinical trials. Given that perioperative ARF remains a common and ominous complication, further large-scale investigation into effective means of prevention is warranted.
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References |
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TOPArticle appraisedCommentary by D. BraccoReferencesCommentary by J. L....References |
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2 Dickersin, Berline JA. Combining the results of several studies: reporting the results of meta-analyses. In: Lang TA, Secic M (Eds.). How to Report Statistics in Medicine. Annotated Guidelines for Authors, Editors, and Reviewers. Philadelphia: American College of Physicians, 1997: 171–85.
3 Weldon BC, Monk TG. The patient at risk for acute renal failure. Recognition, prevention, and preoperative optimization. Anesthesiol Clin North America 2000; 18: 705–17.[Medline]
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