Meta-Analysis: Low-dose dopamine Increases urine output but does not prevent renal dysfunction or death

Annals of Internal Medicine 2005; 142: 510-524

Issaam Oozeerally

Dopamine

• Catecholamine• Dose dependent effects on systemic and renal

vasculature• At low doses increases renal blood flow and

promotes natriuresis [D1, D2, D4 receptors]• 1st clinical use in heart failure

Purpose

• Evaluate effects of low-dose dopamine c.f placebo /no therapy in patients with or at risk of ARF

Methods: Search strategy

• MEDLINE– 1966 –January 2005

• EMBASE– 1980- January 2005

• CINAHL– 1982 – January 2005

• CANCERLIT– 1975 – Oct 2002

• CENTRAL– 4th quarter 2004

• Renal Health library

Search: MEDLINE

1. Dopamine/low dose dopamine/renal dose dopamine

– Limited to clinical trial and meta-analysis

MEDLINE Search no. 2

1 [Dopamine] 2 [Renal disease] 3 [physiology]

Low Kidney Diseases Kidney Function Tests

Renal Kidney Urine

Kidney Renal circulation

Dose

Limited to RCTs [maximally sensitive strategy]

Rest of the search

• Modification of search from other databases– Strategy not specified – Authors happy to be contacted

• Screened reference lists from articles against recent review articles to identify additional studies

• No language restrictions

Selection

• RCTs/quasi-randomization trials• Any sample size• Low dose dopamine vs. placebo/nil• Outcomes:

– All cause mortality– Requirement for RRT– Renal physiological variables [UO, Creat, CrCl day 1, 2, 3]– Adverse effects

• Studies with pharmacologic co-interventions [e.g. mannitol, diuretics]

• A priori adverse effects:– Ischaemia [myocardial, limb, cutaneous] or arrhythmias

Data Abstraction

• 2 independent reviewers• Study authors contacted if any disagreement– Consensus if persisted

• Agreement for inclusion studies statistically tested [Cohen’s κ]

Validity assessment

• Individual studies methodology looked into– Randomization– Blinding– Outcome assessors– Reasons for withdrawals

• Fluids and diuretic therapies– Standard or equally applied in both arms

• Attempted to contact all authors of selected trials

Exclusion Criteria – 70 studies

• Small sample [3 patients]• Dopamine dose >5mcg• Not randomized cross-over study• Combined intervention c.f control• Duplicate • Wrong topic• Editorial• 4 RCTs without group data available from authors• No additional data provided

Hence

• 3359 patients identified in 61 trials

Data Analysis

• Pooled by outcome– E.g. mortality, RRT

• If different doses of dopamine used data was combined

• Random effects model used• Binary outcomes [RRT, mortality, adverse

effects] reported as relative risk• Summary of relative risk : log scale – Used to calculate weight of study

Data Analysis [cont]

• If heterogeneity between studies; weight was adjusted

• Clinical outcomes occurred infrequently and different statistical tests i.e. effect measures were undertaken– Similar results [not presented]

Data Analysis [cont.]

• Renal physiologic outcomes:– Relative change in dopamine gp c.f. control• Mean values were taken• Lack of standardized data e.g. weight

Data Analysis [cont]

• Between study homogeneity for each pool– [concept when there is more variation than

chance alone]– Calculated statistically [I2 and Cochran Q-test]

Patient profile

• Cardiac surgery• Vascular surgery• Other surgery• Iv Contrast dye• Nephrotoxics• Neonates• Miscellaneous

Data

• Average numbers per trial 40 [12 to 347]• ANZICS trial included [328 patients; multi-

centre]• Only 6 trials used dopamine therapeutically:– Critical illness, contrast, malaria, CHF,

preeclampsia

Data

• Median dopamine dose 2.5 mcg• 31 hours median [0.4 to 192 hours]• 12 trials randomization not reported• 11 trials fluids up to the clinician

Clinical outcomes

• No effect on mortality [0.96] or need for RRT [0.93]– No statistical evidence of heterogeneity

• ANZICS trial and most heavily weighted trial removed and data analysed again– No change

Mortality

RRT

Adverse effects

• Arrhythmias & ischaemia [cutaneous, myocardial, limb]

• 6 MI’s [4 on dopamine]• Statistically not significant

Renal Physiologic Outcomes

• Statistically significant increase in urine output on day 1

• Decrease in creat and increase in creat clearance on day 1

• Substantial heterogeneity

Conclusion

• 24% increase in urine output on day 1– Probably explains continued popularity

• ANZICS trial – same results• ANZICS trial – removal of data• Adverse effects – under reported

Discussion

• Methodology– Search strategies not specified– Age and sample size– Combining dopamine doses

• Stats– If no events arbitrary figure of 0.5 given– Study weight adjusted in presence of

heterogeneity– Use of relative risk