1. 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

2. Dopamine Catecholamine Dose dependent effects on systemic and renal vasculature At low doses increases renal blood flow and promotes natriuresis [D1, D2, D4 receptors] 1 st clinical use in heart failure

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

4. Methods: Search strategy MEDLINE – 1966 –January 2005 EMBASE – 1980- January 2005 CINAHL – 1982 – January 2005 CANCERLIT – 1975 – Oct 2002 CENTRAL – 4 th quarter 2004 Renal Health library

5. Search: MEDLINE 1.Dopamine/low dose dopamine/renal dose dopamine – Limited to clinical trial and meta-analysis

6. MEDLINE Search no. 2 1 [Dopamine]2 [Renal disease]3 [physiology] LowKidney DiseasesKidney Function Tests RenalKidneyUrine KidneyRenal circulation Dose Limited to RCTs [maximally sensitive strategy]

7. 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

8. 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

9. Data Abstraction 2 independent reviewers Study authors contacted if any disagreement – Consensus if persisted Agreement for inclusion studies statistically tested [Cohen’s κ]

10. 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

11. 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

12. Hence 3359 patients identified in 61 trials

13. 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

14. 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]

15. 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

16. Data Analysis [cont] Between study homogeneity for each pool – [concept when there is more variation than chance alone] – Calculated statistically [I 2 and Cochran Q-test]

17. Patient profile Cardiac surgery Vascular surgery Other surgery Iv Contrast dye Nephrotoxics Neonates Miscellaneous

18. 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

19. 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

20. 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

21. Mortality

22. RRT

23. Adverse effects Arrhythmias & ischaemia [cutaneous, myocardial, limb] 6 MI’s [4 on dopamine] Statistically not significant

24. 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

25. 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

26. 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