June 26, 2001

Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomized trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group.

Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J. Lancet 2000;356:2139-143.

Commentary by Richard C. Prielipp, M.D., FCCM

The two groups (dopamine, N = 161; placebo N = 163) were similar in baseline demographic characteristics, degree of illness, mean arterial pressure, use of diuretics, coadministration of nephrotoxic drugs, baseline renal function, and duration of study drug infusion. About two-thirds of the study subjects in both groups were oliguric. The results were unequivocal. There were no differences in urine output, rise in serum creatinine, or the incidence of renal failure (as measured by the necessity of renal replacement therapy) in the two groups. The peak creatinine concentration was 245 � 144 umol/L in the dopamine group, and 249 � 147 umol/L in the placebo patients. Furthermore, the duration of ICU stay, duration of hospital stay, as well as number of patient deaths was similar between the two groups. Dopamine was stopped in seven patients due to arrhythmias. The authors conclude that the use of low-dose dopamine in patients at risk of renal failure does not confer clinically significant protection from renal dysfunction.

Of the many "renal-dose" dopamine studies in the last twenty years, this is one of the best…and certainly one of the largest! The patient entry criteria are clear, and duplicate common clinical indications clinicians cite for initiating dopamine therapy in the perioperative period. Thus, the conclusions of this study are broadly applicable to most situations in which renal-dose dopamine is currently utilized. This study also highlights the fact that dopamine, even infused at low doses, may precipitate arrhythmias or other complications serious enough to terminate its administration. The question remains: why doesn’t dopamine work? Of the many reasons cited for the unfavorable findings regarding studies of renal-dose dopamine, we recently established the tremendous variability in dopamine concentrations produced using fixed-dose infusion protocols, which is the routine in most OR and ICU applications. For instance, in a study of nine healthy male volunteers, published in Anesthesiology last year, we frequently observed subjects in whom infusion of "renal-dose dopamine" (3 ug/kg/min) produced greater plasma concentrations than did an infusion of 10 ug/kg/min in other, similar subjects [3]. We presume that dopamine variability in sick, stressed patients would be even greater than the 75-fold variability we observed in young, healthy, male volunteers [3]. Clearly, "renal-dose dopamine" is NOT the same drug in all patients, and this intrinsic pharmacokinetic variability undoubtedly contributes to an unpredictable pharmacodynamic response.

In addition, as indicated in an editorial by Dr. Helen Galley which accompanied the Lancet article, renal-dose dopamine is not necessarily harmless. Besides the arrhythmogenic effects identified above, dopamine can suppress the respiratory drive, produce tachycardia and increase myocardial oxygen consumption, induce electrolyte imbalances such as hypokalemia and hypophosphatemia, alter prolactin homeostasis and immunologic function, and may cause local ischemia and gangrene if it extravasates outside of a peripheral intravenous catheter.

Supplemental Information:

Additional Aspects of Dopamine therapy:

• Preoperative dehydration and enhanced tubular Na reabsorption can completely overcome the diuretic effect of low-dose dopamine.
• Dopamine may protect renal tubules by suppressing the sodium pump, decreasing V0₂ and increasing tubular flow. However, as noted above, no clinical studies confirm that prophylactic administration prevents renal injury.
• Dopamine increases renal clearance of aminoglycoside antibiotics, reverses low renal blood flow caused by oral cyclosporin A, and prevents renal damage induced by recombinant interleukin-2 therapy for metastatic urologic cancer.
• In infrarenal aortic cross-clamping, dopamine enhances urine flow but is not more effective in maintaining glomerular filtration rate (GFR) than aggressive saline administration.
• In a prospective study on patients undergoing orthotopic liver transplantation, prophylactic low dose dopamine had no effect on intraoperative urine flow, postoperative GFR, incidence of acute renal failure, or mortality.
• In cadaveric renal transplantation, dopamine increases urine flow but postoperative GFR and dialysis requirement remain unchanged.
• In chronic renal disease, dopamine has a diuretic effect but does not increase GFR when the baseline GFR is <50 ml/min/m²

The Pathophysiology of Acute Tubular Necrosis

Ischemic or nephrotoxic acute tubular necrosis (ATN) is a process, which can be divided into three phases: initiation, maintenance, and recovery. Although ATN is usually reversible, severe hypoperfusion or toxic insults will result in cortical necrosis and irreversible failure. Many factors affect the oxygen supply/demand balance within the renal tubules, and some of these factors are outlined in the table below.

Following an ischemic insult during the initiation phase, cellular injury occurs which results in a loss of polarized features, disruption of active transport mechanisms, and loss of tight junctional integrity of the tubular epithelium. Eventually, the necrotic epithelial cells slough into the tubules interfering with urine flow and causing back leak of glomerular filtrate. In all cases of oliguria or renal dysfunction, patient exposure to additional nephrotoxins such as those listed below should be avoided whenever possible.

COMMON NEPHROTOXINS

References:

• Ichai C, Soubielle J, Carles M, Giunti C, Grimaud D. Comparison of the renal effects of low to high doses of dopamine and dobutamine in critically ill patients: A single-blind randomized study. Crit Care Med 2000;28:921-928.
  Click here for abstract
• Duke GJ, Briedis JH, Weaver RA. Renal support in critically ill patients: Low-dose dopamine or low-dose dobutamine? Crit Care Med 1994;22:1919-1925.
  Click here for abstract
• MacGregor DA, Smith TE, Prielipp RC, et al. Pharmacokinetics of dopamine in healthy male subjects. Anesthesiology 2000;92:338-346 (plus editorial).
  Click here for abstract

Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomized trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group.

AUTHORS:
Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J.

SOURCE:
Lancet 2000;356:2139-143.

ABSTRACT:

BACKGROUND: Low-dose dopamine is commonly administered to critically ill patients in the belief that it reduces the risk of renal failure by increasing renal blood flow. However, these effects have not been established in a large randomised controlled trial, and use of dopamine remains controversial. We have done a multicentre, randomised, double-blind, placebo-controlled study of low-dose dopamine in patients with at least two criteria for the systemic inflammatory response syndrome and clinical evidence of early renal dysfunction (oliguria or increase in serum creatinine concentration).

METHODS: 328 patients admitted to 23 participating intensive-care units (ICUs) were randomly assigned a continuous intravenous infusion of low-dose dopamine (2 microg kg(-1) min(-1)) or placebo administered through a central venous catheter while in the ICU. The primary endpoint was the peak serum creatinine concentration during the infusion. Analyses excluded four patients with major protocol violations.

FINDINGS: The groups assigned dopamine (n=161) and placebo (n=163) were similar in terms of baseline characteristics, renal function, and duration of trial infusion. There was no difference between the dopamine and placebo groups in peak serum creatinine concentration during treatment (245 [SD 144] vs 249 [147] micromol/L; p=0.93), in the increase from baseline to highest value during treatment (62 [107] vs 66 [108] micromol/L; p=0.82), or in the numbers of patients whose serum creatinine concentration exceeded 300 micromol/L (56 vs 56; p=0.92) or who required renal replacement therapy (35 vs 40; p=0.55). Durations of ICU stay (13 [14] vs 14 [15] days; p=0.67) and of hospital stay (29 [27] vs 33 [39] days; p=0.29) were also similar. There were 69 deaths in the dopamine group and 66 in the placebo group.

INTERPRETATION: Administration of low-dose dopamine by continuous intravenous infusion to critically ill patients at risk of renal failure does not confer clinically significant protection from renal dysfunction.