1. Pharmacological pre-emptive strategies to reduce peri-operative risk: give me the magic bullet, please Speaker:Landoni G INTERCEPT 2009 S Donato Milanese, Milan, April 17h 2009 IRCCS Ospedale San Raffaele Milano Università Vita-Salute San Raffaele

2. MAGIC BULLETS TO REDUCE MORTALITY IN CARDIAC SURGERY zTHERE ARE NO GUIDELINES zTHERE IS NO CONSENSUS CONFERENCE zTHERE IS NO LARGE RANDOMIZED CONTROLLED STUDY ADEQUATELY POWERED TO SUGGEST A REDUCTION IN MORTALITY

3. AN OVERVIEW OF META-ANALYSIS zPEXELIZUMAB zLEVOSIMENDAN zFENOLDOPAM zVOLATILE AGENTS (Intercept 2006)

4. AN OVERVIEW OF META-ANALYSIS zMAGIC BULLET zPEXELIZUMAB zLEVOSIMENDAN zFENOLDOPAM zVOLATILE AGENTS z NNT TO PREVENT ONE DEATH z 100 z 12 z 19 or 26 z 84

7. LEVOSIMENDAN 1

11. LEVOSIMENDAN 2

12. Description of the ten studies included in the meta-analysis. First authorJournalYearCardiac surgery proceduresControl Al-ShawafJ Cardiothorac Vasc Anesth2006Elective CABG*Milrinone Alvarez 2005Rev Esp Anestesiol Reanim2005Cardiac surgery with CPB†Dobutamine Alvarez 2006Rev Esp Cardiol2006Cardiac surgery with CPB†Dobutamine BarisinJ Cardiovasc Pharmacol2004OPCABG‡Placebo De Hert 2007Anesth Analg2007Elective cardiac surgery with CPB†Milrinone De Hert 2008J Cardiothorac Vasc Anesth2008Cardiac surgery with CPB†Milrinone HusedzinovicCroat Med J2005OPCABG‡Placebo JarvelaJ Cardiothorac Vasc Anesth2008Aortic valve surgeryPlacebo LevinRev Esp Cardiol2008CABG* with CPB†Dobutamine TritapepeBr J Anaesth2006CABG* with CPB†Placebo * CABG: coronary artery bypass graft † CPB: cardiopulmonary bypass ‡ OPCABG: off-pump coronary artery bypass graft

13. Number of patients and interventions of included studies. First authorTime of administration Setting Bolus doseContinuous infusion doseLength of infusion Al-ShawafLCOS # 12  g/kg0.1-0.2  g/kg/min 24 hours Alvarez 2005LCOS # 12  g/kg0.2  g/kg/min 24 hours Alvarez 2006LCOS # 12  g/kg0.2  g/kg/min 24 hours BarisinBefore surgery 12/24  g/kg no De Hert 2007After CPB†No bolus 0.1  g/kg/min 19+4 hours De Hert 2008 First group : after induction of anesthesia Second group : after CPB† No bolus 0.1  g/kg/min 22+4 hours in the first group, 23+3 hours in the second one HusedzinovicBefore surgery 12  g/kg no JarvelaAfter inductionNo bolus 0.2  g/kg/min 24 hours LevinLCOS # 10  g/kg0.1  g/kg/min 24 hours TritapepeBefore CPB† 24  g/kg no † CPB: cardiopulmonary bypass # LCOS: low cardiac output syndrome

14. Levosimendan and Mortality in Cardiac Surgery

15. 711/235=4.7% v 26/205=12.7% 7P=0.007 7NNT = 12 Levosimendan and Mortality in Cardiac Surgery

16. Levosimendan and Myocardial Infarction

17. LEVOSIMENDAN VS CONTROL Myocardial Infarction in cardiac surgery 72/183=1.1% v 9/153=5.9% 7P=0.04 Evidence!

18. Levosimendan and Acute Renal Failure NNT = 6

19. LEVOSIMENDAN 2

20. ITACTA ONGOING RCTs TOPICSHOSPITALSPATIENTS GRANTS zVOLATILE ANESTHETICS zFENOLDOPAM zDESMOPRESSIN zESMOLOL zLEVOSIMENDAN zVALVOLE PERCUTANEE landoni.giovanni@hsr.it www.itacta.org z 4200AIFA 2006 z 341.000MINISTRY 2008 z 3200 z 101.000 z 3150

21. AIM OF THE STUDY To evaluate the renoprotective action of fenoldopam in a selected high-risk group of patients undergoing cardiac surgery

22. RESULTS Variables Fenoldopam N=40 Dopamine N=40 p ARF (25%Creatinine increase), n(%) 17(42.5%)16(40.0%)0.9 ARF (50% Creatinine increase), n(%) 10(25%) 0.8 Renal Replacement Therapy.,n(%) 4(10%) 0.9 Exitus,n(%) 4(10%)3(7.5%) 0.5 Transfusion,n(%)21(56.8)18(51.4)0.8 Post-operative inotropes,n(%) 27(67.5)26(65.0)0.9 Post-operative hemolysis,n(%) 6(15)1(2.5)0.054 Mechanical ventilation hours 20.5(11.5-77)21(10.5-96)0.7 ICU stay,days3(1-6)3(1-8.5)0.9 Hospital stay,days13(7-19)10.5(6-20.5)0.8 zPost-operative data

23. Am J Kidney Dis. 2007;4956-68. IF 4.4

24. Fenoldopam and Death in Critically ill patients 81/487(17%) versus 109/531 (21%) p=0.01 NNT=26

25. Pooled estimates of risk for need for renal replacement therapy 34/526 (6%) versus 59/570 (10%)p=0.007 NNT=26

27. Fenoldopam and Death in Cardiovascular Surgery 28/503 (6%) versus 55/503 (11%) p=0.002 NNT=19

28. Fenoldopam and renal replacement therapy in cardiovascular surgery 30/528 (6%) versus 71/531 (13%)p<0.001 NNT=13

29. ITACTA ONGOING RCTs TOPICSHOSPITALSPATIENTS GRANTS zVOLATILE ANESTHETICS zFENOLDOPAM zDESMOPRESSIN zESMOLOL zLEVOSIMENDAN zVALVOLE PERCUTANEE landoni.giovanni@hsr.it www.itacta.org z 4200AIFA 2006 z 341.000MINISTRY 2008 z 3200 z 101.000 z 3150

30. FENO-HSR FENOLDOPAM E INSUFFICIENZA RENALE

31. Fenoldopam vs placebo randomized double blind multicenter (32 centers, 1000 patients) DESIGN

32. “R” (RIFLE) after cardiac surgery Which patients? Serum creatinine increase by 50% or Urinary output <0,5 ml/kg/h for 6 h Planned ICU stay > 24 hours

33. AIM OF THE STUDY Reduction of the need for renal replacement therapy From 10% to 5%

34. DESFLURANE versus PROPOFOL (fentanyl-based cardiac anesthesia)

35. RCT (382 PATIENTS) OFF-PUMP CABG (112 PATIENTS) ON-PUMP CABG (150 PATIENTS) MITRAL SURGERY (120 PATIENTS)

39. Peak TROPONIN I ng/ml OFF-PUMP CABG 1.2 (0.9-1.9) versus 2.7 (2.1-4.0) *P<0.001 ON-PUMP CABG 2.5 (1.1-5.3) versus 5.5 (2.3-9.5) *P<0.001 MITRAL SURGERY 11.0 (7.5-17.4) versus 11.5 (6.9-18.8) P=0.7

40. Troponin I after OFF-PUMP CABG

41. Troponin I after CABG (CPB)

42. Troponin I after MITRAL SURGERY

44. Volatile Anesthetics

45. META-ANALYSIS (cardiac anaesthesia) 422 randomized studies (15 CPB-CABG; 6 OP-CABG; 1 mitral valve surgery) 41922 patients (904 TIVA and 1018 DES or SEVO) 416 studies administered volatile anesthetics throughout all the procedure (6 studies for 5-30 minutes)

46. Mortality Evidence!

47. Mortality 74/977=0.4% v 14/872=1.6% 7NNT=84 7RRR=(1,6-0,4)/1,6=75% 7OR: 0.31(0.12-0.80) 7P=0.02 Evidence!

48. Myocardial infarction Evidence!

49. 724/979=2.4% v 45/874=5.1% 7NNT=37 7RRR: (5.1-2.4)/5.1 = 53% 7OR: 0.51(0.32-0.84) 7p=0.008 Myocardial infarction Evidence!

52. DURATION OF USE OF INHALATORY ANESTHETICS DURING SURGERY RISK-ADJUSTED MORTALITY (%) 8 6 4 2 0 NO USE ALL OF THE OPERATION ONLY INCISION/ STERNOTOMY PART OF THE OPERATION P=0.022

53. RISK-ADJUSTED MORTALITY (%) P=0.007 8 6 4 2 0 USE OF INHALATORY ANESTHETICS 0% TO <50% OF CASES ≥50% OF CASES P=0.007

56. NON-CARDIAC SURGERY

57. Volatile Anesthetics Cardioprotection & anaesthesia Volatile Anesthetics   blockers “recommended” CStatins“suggested” in selected pts   2 agonists “may be considered” in selected pts CCa ++ antagonists“may be considered” in selected pts CInsulin“reasonable” in hyperglycaemic pts CVolatile Anesthetics “can be beneficial”

59. Every 1.000 patients receiving extended release METOPROLOL zPREVENTION OF 15 MYOCARDIAL INFARCTON zPREVENTION OF 3 CABG zPREVENTION OF 7 ATRIAL FIBRILLATION

60. Every 1.000 patients receiving extended release METOPROLOL zEXCESS OF 8 DEATHS zEXCESS OF 5 STROKE zEXCESS 53 HYPOTENSION zEXCESS 42 BRADICARDIA

63. A meta-analysis in noncardiac surgery 6219 patients 2842 sevoflurane 609 desflurane 2768 propofol Evidence?

64. Total79 Anesth analg 20 BJA14 EJA11 Acta anaesthesiol scand8 Anaesthesia5 J Anesth4 Anesthesiology3 Minerva anestesiol2 Altri13 A meta-analysis in noncardiac surgery Evidence?

65. 4400 authors 4240 reviewers 490 editors 0 deaths 0 myocardial infarctions A meta-analysis in noncardiac surgery Evidence?

66. TAKE HOME MESSAGE zMAGIC BULLET zPEXELIZUMAB zLEVOSIMENDAN zFENOLDOPAM zVOLATILE AGENTS z NNT TO PREVENT ONE DEATH z 100 z 12 z 19 or 26 z 84

67. “PERCHE’ NON SIAM POPOLO PERCHE’ SIAM DIVISI” MAMELI

68. ITACTA ONGOING RCTs TOPICSHOSPITALSPATIENTS GRANTS zVOLATILE ANESTHETICS zFENOLDOPAM zDESMOPRESSIN zESMOLOL zLEVOSIMENDAN zVALVOLE PERCUTANEE landoni.giovanni@hsr.it www.itacta.org z 4200AIFA 2006 z 341.000MINISTRY 2008 z 3200 z 101.000 z 3150

69. GRUPPI DI INTERESSE ITACTA (COORDINATI DA ANESTESISTI UNDER 40) Gruppi esistenti ad oggi 27-3-2009 (per piu’ informazioni www.itacta.org), aperti ad iscrizioni www.itacta.org z1. Sostituzioni valvolari percutanee (covello.remodaniel@hsr.it)covello.remodaniel@hsr.it z2. Monitoraggio emodinamico mini-invasivo (giuliamaj@hotmail.com)giuliamaj@hotmail.com z3. Statistica in anestesia e terapia intensiva (monaco.fabrizio@hsr.it)monaco.fabrizio@hsr.it z4. Analgesia selettiva in chirurgia toracica (drpiraccini@gmail.com)drpiraccini@gmail.com

71. For these and further slides on these topics please feel free to visit the metcardio.org website: http://www.metcardio.org/slides.html http://www.metcardio.org/slides.html