Publication

• Title: Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial
• Acronym: Not applicable
• Year: 2000
• Journal published in: Lancet
• Citation: Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J; Australian and New Zealand Intensive Care Society Clinical Trials Group. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Lancet. 2000;356:2139-2143.

Context & Rationale

• Background

  “Renal-dose” dopamine (typically 1–3 μg/kg/min) was widely used in critical care to increase renal blood flow, augment urine output, and prevent progression from early renal dysfunction to acute renal failure.
• Research Question/Hypothesis

  In critically ill adults with systemic inflammatory response syndrome (SIRS) and early renal dysfunction, does continuous low-dose dopamine reduce biochemical worsening of renal function (primary: peak serum creatinine during infusion), and improve clinically important renal outcomes (renal replacement therapy) and mortality, compared with placebo?
• Why This Matters

  Because dopamine was being administered at scale to high-risk ICU patients on physiological grounds, a definitive blinded randomised trial in the intended target population was needed to determine whether “renal protection” was real, clinically meaningful, and safe.

Design & Methods

• Research Question: Does continuous low-dose dopamine (2 μg/kg/min) improve renal function (peak creatinine during infusion) and renal/outcome endpoints versus placebo in ICU patients with SIRS and early renal dysfunction?
• Study Type: Multicentre, randomised, double-blind, placebo-controlled trial conducted in 23 intensive care units (Australia and New Zealand); enrolment March 1996 to April 1999.
• Population:
  • Setting: ICU patients with a central venous catheter in situ.
  • Inclusion criteria: Adults with ≥2 SIRS criteria in the prior 24 h (temperature >38°C or <36°C; heart rate >90/min; respiratory rate >20/min or PaCO₂ <4.3 kPa; white cell count >12×10⁹/L or <4×10⁹/L or >10% bands).
  • Early renal dysfunction entry criteria: At least one of the following: urine output <0.5 mL/kg/h for ≥4 h; or serum creatinine >150 μmol/L with no premorbid renal dysfunction; or rise in creatinine >80 μmol/L in <24 h without creatine kinase >5000 IU/L and without myoglobinaemia.
  • Key exclusions: Age <18 years; episode of acute renal failure in prior 3 months; previous renal transplant; dopamine use at any dose during current ICU stay; baseline creatinine >300 μmol/L; inability to administer trial drug for ≥8 h; unsuitability for renal replacement therapy.
• Intervention:
  • Continuous intravenous dopamine infusion at 2 μg/kg/min via the central venous catheter.
  • Study infusion prepared by an independent pharmacist/nurse not involved in bedside care; prepared at a separate site; replaced every 24 h.
• Comparison:
  • Identical-appearing placebo infusion administered with the same procedures and replacement schedule.
  • Co-interventions (including diuretics, nephrotoxic drugs, ventilation, vasopressors) were not protocolised beyond usual ICU practice and were recorded.
• Blinding: Double-blind (patients, clinicians, and investigators); allocation concealed via an independently held randomisation schedule; study drug and placebo were indistinguishable at the bedside.
• Statistics: Power calculation: 115 patients per group were required to detect a 20% reduction in peak creatinine (assumed mean ~250 μmol/L) with 80% power at a 5% significance level; after planned interim analyses at 100 and 200 patients, the sample size was increased to >300 to increase power (final design stated ~90% power to detect >25% difference at 5% significance); primary analyses were performed in a modified intention-to-treat population excluding 4 patients with major protocol violations/withdrawals.
• Follow-Up Period: Renal endpoints assessed during the infusion period; time-to-renal recovery assessed with Kaplan–Meier methods; clinical outcomes assessed to ICU discharge and hospital discharge.

Key Results

This trial was not stopped early. Planned interim analyses occurred (after 100 and 200 patients) and the total sample size was increased; the trial completed recruitment (328 randomised; 324 analysed).

• The intervention delivered a canonical “renal-dose” dopamine regimen, yet peak creatinine was virtually identical between groups (245 vs 249 μmol/L; P=0.93), with tight confidence limits inconsistent with any clinically important renal biochemical benefit.
• Clinical renal endpoints were frequent (renal replacement therapy in 35 vs 40 patients), but were not improved by dopamine (P=0.55), and mortality was high (69/161 vs 66/163; P=0.66).
• Urine output profiles and renal recovery curves did not diverge, arguing against even transient “diuretic” renal protection translating into outcome benefit.

Internal Validity

• Randomisation and allocation concealment: Allocation sequence held by an independent pharmacist/nurse; drug preparation off-ward with identical infusions; concealment and blinding were plausibly robust.
• Drop out/exclusions: 328 randomised; 4 patients withdrawn/excluded post-randomisation (2 in dopamine arm; 2 in placebo arm), yielding 161 vs 163 analysed; the symmetric attrition reduces (but does not eliminate) risk of attrition bias.
• Performance/detection bias: Primary and major secondary outcomes were objective laboratory values and hard clinical endpoints (renal replacement therapy, mortality), reducing susceptibility to detection bias in a blinded design.
• Protocol adherence: Mean infusion duration was similar (113 [157] h vs 125 [166] h; P=0.45); study drug discontinuation for suspected arrhythmia was identical (7 vs 7), supporting similar thresholding across groups.
• Baseline comparability: Groups were well matched in severity (APACHE II at infusion start 18 [7] vs 18 [7]), shock prevalence (93 vs 102), ventilation at infusion start (138 vs 141), and baseline creatinine (183 [85] vs 182 [81] μmol/L).
• Heterogeneity: Broad ICU diagnostic mix and high acuity improve pragmatic relevance but increase within-group variance; nevertheless, treatment effect was null with confidence limits excluding clinically meaningful benefit on the primary endpoint.
• Timing: Entry criteria targeted early renal dysfunction (oliguria or rising creatinine) in the context of SIRS, aligning with the hypothesised “prevention” window; exact time from onset to infusion start was not reported in sufficient granularity.
• Dose: 2 μg/kg/min reflects standard “renal-dose” practice; however, dopamine pharmacodynamics in critical illness (receptor downregulation, competing vasopressor exposure, microcirculatory dysfunction) may blunt any renal vasodilatory effect even if present in health.
• Separation of the variable of interest: Biochemical renal separation was absent (peak creatinine 245 [144] vs 249 [147] μmol/L); urine output at 1 h was similar (71 [81] vs 72 [77] mL/h) and at 48 h remained similar (99 [83] vs 109 [95] mL/h).
• Crossover/contamination: Dopamine use at any dose during the ICU stay was an exclusion criterion; crossover to open-label dopamine for “renal protection” should therefore have been minimised (explicit crossover rates not reported).
• Adjunctive therapies: Furosemide exposure was similar (192 [464] mg vs 268 [714] mg; P=0.39), and nephrotoxin exposure was reported as comparable, limiting confounding by differential renal-directed co-intervention.
• Statistical rigour: Pre-specified power focused on a surrogate primary endpoint; confidence intervals for key renal markers were narrow and centred near zero, supporting a robust “no clinically relevant effect” conclusion for renal biochemistry; the trial remained underpowered for small mortality differences.

Conclusion on Internal Validity: Strong for the primary biochemical renal endpoint (concealed randomisation, double blinding, objective outcome, minimal symmetric attrition), and moderate for clinical endpoints where power was limited (renal replacement therapy and mortality).

External Validity

• Population representativeness: High-acuity ICU patients with SIRS and early renal dysfunction (many ventilated, many in shock) reflect the population in whom “renal-dose dopamine” was commonly used.
• Important exclusions: Baseline creatinine >300 μmol/L; recent acute renal failure episode; previous renal transplant; and patients unsuitable for renal replacement therapy—these exclusions limit inference in advanced AKI, chronic kidney disease/transplant cohorts, and patients receiving ceiling-of-care approaches.
• Applicability across systems: Conducted across 23 ICUs, supporting generalisability to similar high-resource ICUs with access to renal replacement therapy; applicability may be reduced in resource-limited settings where dialysis availability and thresholds differ.
• Clinical practice translation: The intervention dose and delivery mimic routine practice (continuous low-dose infusion), enhancing implementation relevance; however, contemporary vasopressor practices have evolved, potentially altering background risk and co-interventions.

Conclusion on External Validity: Findings are broadly generalisable to adult, high-acuity ICU patients with SIRS and early renal dysfunction in systems where renal replacement therapy is available, but less directly applicable to advanced AKI, transplant populations, and settings with constrained dialysis access.

Strengths & Limitations

• Strengths: Pragmatic multicentre ICU design; double-blind placebo control; enrolment of a clearly high-risk population (high dialysis and mortality rates); objective primary endpoint with narrow confidence limits; clinically important renal endpoints (renal replacement therapy) captured.
• Limitations: Primary endpoint was a surrogate marker rather than a patient-centred clinical outcome; limited power for mortality and modest differences in renal replacement therapy; post-randomisation exclusions (modified intention-to-treat) rather than strict intention-to-treat; background co-interventions not protocolised (reflecting usual care but introducing practice variability).

Interpretation & Why It Matters

• Renal “protection” was not demonstrated

  At a dose designed to selectively target dopaminergic receptors, low-dose dopamine did not reduce peak creatinine, did not reduce progression to severe creatinine thresholds, and did not reduce the requirement for renal replacement therapy.
• Clinical practice implication

  In a population where renal dysfunction frequently progressed and outcomes were poor, the absence of benefit on renal biochemistry and clinically important renal endpoints supports abandoning routine renal-dose dopamine as a renoprotective strategy.
• Mechanistic recalibration

  The trial undermines the assumption that dopamine-induced diuresis (if present) is equivalent to renal protection; urine output is not a reliable surrogate for preservation of glomerular filtration or avoidance of dialysis in critical illness.

Controversies & Subsequent Evidence

• The accompanying Lancet editorial emphasised that the physiological “renal-dose dopamine” narrative persisted despite accumulating negative clinical data, and highlighted plausible off-target harms (endocrine, immune, regional perfusion) that further weaken the risk–benefit proposition.¹
• A later meta-analysis across randomised trials concluded that low-dose dopamine may increase urine output but does not prevent renal dysfunction, renal replacement therapy, or death—reinforcing the message that diuresis is not a surrogate for clinically meaningful renal benefit.²
• KDIGO guidance recommends against low-dose dopamine for prevention or treatment of acute kidney injury, positioning this therapy as unsupported and potentially harmful in contemporary AKI care pathways.³
• Surviving Sepsis Campaign guidance prioritises norepinephrine as first-line vasopressor and de-emphasises dopamine; “renal-dose” dopamine is not supported as a renoprotective adjunct in septic critical illness management frameworks.⁴
• Subsequent trials in other high-risk populations (e.g., acute heart failure with renal dysfunction) similarly failed to show renal benefit from low-dose dopamine, suggesting the negative signal is not confined to ICU SIRS cohorts.⁵

Summary

• In 23 ICUs, low-dose dopamine (2 μg/kg/min) in adults with SIRS and early renal dysfunction did not reduce peak creatinine versus placebo (245 vs 249 μmol/L; P=0.93).
• Dopamine did not reduce clinically important renal endpoints (renal replacement therapy 35 vs 40 patients; P=0.55) and did not improve survival to hospital discharge (69/161 vs 66/163 deaths; P=0.66).
• Urine output trajectories and renal recovery curves were not meaningfully different, undermining “diuresis equals renal protection” assumptions.
• Internal validity for the primary endpoint was strong (double-blind, concealed allocation, objective labs, minimal symmetric attrition).
• The trial helped catalyse a shift away from routine “renal-dose dopamine”, later reinforced by meta-analyses and guideline recommendations against its use for AKI prevention/treatment.

Further Reading

Other Trials

• 2013Chen 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 randomised trial. JAMA. 2013;310:2533-2543.
• 2002Woo EBC, Tang AT, El-Gamel A, et al. Dopamine therapy for patients at risk of renal dysfunction following cardiac surgery: Science or fiction? Eur J Cardiothorac Surg. 2002;22:106-111.
• 2000Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J; Australian and New Zealand Intensive Care Society Clinical Trials Group. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Lancet. 2000;356:2139-2143.

Systematic Review & Meta Analysis

• 2005Friedrich JO, Adhikari NKJ, 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.
• 2002ACP Journal Club. Review: low-dose dopamine does not prevent renal dysfunction or death in critically ill patients. Ann Intern Med. 2002;136:JC1-3.

Observational Studies

• 1999Burton CJ, Tomson CRV. Can the use of low-dose dopamine for treatment of acute renal failure be justified? Nephrol Dial Transplant. 1999;14:2932-2938.

Guidelines

• 2021Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Intensive Care Med. 2021;47:1181-1247.
• 2012Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl. 2012;2:1-138.

Overall Takeaway

This multicentre blinded trial directly tested routine “renal-dose” dopamine in the ICU population it was intended for and found no renal biochemical benefit, no reduction in renal replacement therapy, and no improvement in mortality. It is a landmark because it helped move practice from physiological plausibility to outcome-based evidence, and it underpins modern guidance that low-dose dopamine should not be used as a renoprotective strategy.

Bibliography

• Galley HF. Renal-dose dopamine: will the message now get through? Lancet. 2000;356:2112-2113.
• Friedrich JO, Adhikari NKJ, 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.
• Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl. 2012;2:1-138.
• Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Intensive Care Med. 2021;47:1181-1247.
• 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 randomised trial. JAMA. 2013;310:2533-2543.