1. 1 TREATMENT STRATEGIES FOR AKI AFTER CPB (FENOLDOPAM, EARLY PD) STEFANO PICCA and ZACCARIA RICCI Dialysis Unit- Dept of Nephrology and Urology CICU- Dept of Cardiology, “Bambino Gesù” Pediatric Research Hospital ROMA, Italy

2. In post- heart surgery AKI, which is (are?) the time window (windows?) suitable for a worthy intervention? OUTLINE Peritoneal Dialysis in pediatric post-heart surgery AKI Does PD provide inflammation mediators removal? Does PD provide suitable fluid removal? Fenoldopam in pediatric post-heart surgery AKI Does Fenoldopam provide “nephroprotection” ? What Fenoldopam dosages are required to induce “nephroprotection”?

3. TIME WINDOWS FOR AKI MANAGEMENT RRT Nephroprotection? Modified from Sutton, 2002 Fluids Drugs Diuretics

4. 61 children/2262 CPB heart surgery operations underwent PD (2.7%) Time from end of surgery to PD start: 2 hrs - 15 days (median 24 hrs) 48/61 (79%) did not survive

7. authornTime to PD startPts with negative fluid balance Survivors Lowrie (2000)17NA35%24% Fleming (1995)212.5 days (1-6) after surgery 36%38% Golej (2002)116NA, but 43% of pts started on PD when CVP>10 mmHg 53%47% Werner (1996)232.6±0.6 days100%53% Santos (2012)234.8±16.8 hrs100%56.6% Chien (2009)71.2±0.4 days after AKI onset NA57% Dittrich (1999)27In the OR or first hrs in ICU 100%73% Sorof (1999)2022 hrs100%80% PD AFTER HEART SURGERY IN CHILDREN: FLUID BALANCE AND SURVIVAL THROUGH THE YEARS

8. PD in 146 neonates and infants after surgery “early” PD: at the end of surgery or day after surgery Significant better survival at 30 and 90 days with early PD Unfortunately, no fluid overload measurement

9. Bojan, Kidney Int, 2012

10. FENOLDOPAM AND NEPHROPROTECTION: MECHANISM FENOLDOPAM MESYLATE Short-acting selective DA- 1 dopaminergic receptor agonist INDUCES: Increased cAMP-PKA production in renal arteries smooth muscle: arterial relaxation and increased renal blood flow Increased cAMP concentration in tubular cells and inhibition of Na-H and Na-K ATPase: increased natriuresis Decreased aldosterone production: increased natriuresis M Ranucci Minerva Anestesiol 2010 Z Ricci Interact CardioVasc Thorac Surg 2008

11. PCCM 2006

12. LIMITATIONS: RANDOMIZATION FENOLDOPAM 0,1 mcg/Kg/min LATE AKI MARKERS WITH LOW SENSIBILITY AND SPECIFICITY Fenoldopam in newborn patients undergoing cardiopulmonary bypass: controlled clinical trial Ricci Z et al. Interactive CardioVascular and Thoracic Surgery 7 (2008) 1049–1053

13. 80 patients (<1 yr) 40 group F 40 group C Fenoldopam 1mcg/kg/min Placebo No difference: Age BW Heart defect RACHS score and operation duration CPB, PAM, mean CPB flow, mean Hb media and lowest T in CPB Inotropic score RESULTS (1)

14. RESULTS (2) No difference between group F and controls in: Plasma NGAL and CysC plasma creatinine levels and urine output pRIFLE 50% in group F and 72% in group P (p = 0.08) Inotropic score ISVR and IDO 2 Significant difference between group F and controls in: Furosemide and phentolamine administration in group F (p = 0.0085)

15. In pediatric post-heart surgery AKI, early PD can provide better survival than late PD application This occurs in spite of less performing fluid removal and consequent worst nutrition management compared with CRRT Early fluid overload management and/or the less negative patient selection are probably the clue issues to explain this CONCLUSIONS (1)

16. In pediatric open-heart surgery, Fenoldopam at 1 mcg/kg/min during CPB is safe With this dosage, Fenoldopam is able to prevent the acute rise of proved urinary AKI markers Patients treated with Fenoldopam require lower diuretic and vasodilator dosages than controls Although high- dose Fenoldopam cannot still be recommended in all children undergoing heart surgery, it potentially represents a nephroprotection in these patients. CONCLUSIONS (2)

17. stefano.picca@opbg.net

18. CRRT AND PD IN PEDIATRIC POST-HEART SURGERY AKI: PROS AND CONS Fluid removal Caloric intake applicationanticoagulationCV tolerancecosts CRRTHigher complexneededPossibly worsthigh PDlower easynonePossibly betterlow No prospective study has evaluated the effect of dialysis modality on the outcome of children with AKI in the ICU setting.

19. HIGH DOSE FENOLDOPAM CONTROLLED STUDY: METHODS INCLUSION CRITERIA: Age < 1 yr Correction in biventricular anatomy RACHS > 1 CPB EXCLUSION CRITERIA DHCA Pre-surgery high creatinine levels Rx: High dose fenoldopam (1 mcg/kg/min) during CPB Primary Outcomes: Decreased NGAL and Cystatin C urine levels Increased UO and decreased plasma creatinine Decreased diuretics and vasodilator drugs

20. Time AKI mortality FO CRRT? PD? PD CRRT PD IN AKI: LIMITED FLUID REMOVAL AND (LOGICAL) EARLY APPLICATION