IRCCS Ospedale San Raffaele Milano Universit VitaSalute San

IRCCS Ospedale San Raffaele Milano Università Vita-Salute San Raffaele 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 17 h 2009

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

AN OVERVIEW OF META-ANALYSIS z. PEXELIZUMAB z. LEVOSIMENDAN z. FENOLDOPAM z. VOLATILE AGENTS (Intercept 2006)

AN OVERVIEW OF META-ANALYSIS z MAGIC BULLET z NNT TO PREVENT ONE DEATH z PEXELIZUMAB z LEVOSIMENDAN z FENOLDOPAM z VOLATILE AGENTS z 100 z 12 z 19 or 26 z 84

LEVOSIMENDAN 1

LEVOSIMENDAN 2

Description of the ten studies included in the meta-analysis. First author Journal Year Cardiac surgery procedures Control Al-Shawaf J Cardiothorac Vasc Anesth 2006 Elective CABG* Milrinone Alvarez 2005 Rev Esp Anestesiol Reanim 2005 Cardiac surgery with CPB† Dobutamine Alvarez 2006 Rev Esp Cardiol 2006 Cardiac surgery with CPB† Dobutamine Barisin J Cardiovasc Pharmacol 2004 OPCABG‡ Placebo De Hert 2007 Anesth Analg 2007 Elective cardiac surgery with CPB† Milrinone De Hert 2008 J Cardiothorac Vasc Anesth 2008 Cardiac surgery with CPB† Milrinone Husedzinovic Croat Med J OPCABG‡ Placebo Jarvela J Cardiothorac Vasc Anesth 2008 Aortic valve surgery Placebo Levin Rev Esp Cardiol 2008 CABG* with CPB† Dobutamine Tritapepe Br J Anaesth 2006 CABG* with CPB† Placebo * CABG: coronary artery bypass graft † CPB: cardiopulmonary bypass ‡ OPCABG: off-pump coronary artery bypass graft 2005

Number of patients and interventions of included studies. First author Time of administration Setting Bolus dose Continuous infusion dose Length of infusion Al-Shawaf LCOS# 12 mg/kg 0. 1 -0. 2 mg/kg/min 24 hours Alvarez 2005 LCOS# 12 mg/kg 0. 2 mg/kg/min 24 hours Alvarez 2006 LCOS# 12 mg/kg 0. 2 mg/kg/min 24 hours Barisin Before surgery 12/24 mg/kg no no No bolus 0. 1 mg/kg/min 19+4 hours No bolus 0. 1 mg/kg/min 22+4 hours in the first group, 23+3 hours in the second one Husedzinovic Before surgery 12 mg/kg no no Jarvela After induction No bolus 0. 2 mg/kg/min 24 hours Levin LCOS# 10 mg/kg 0. 1 mg/kg/min 24 hours Tritapepe Before CPB† 24 mg/kg no no De Hert 2007 After CPB† De Hert 2008 First group : after induction of anesthesia Second group : after CPB† † CPB: cardiopulmonary bypass # LCOS: low cardiac output syndrome

Levosimendan and Mortality in Cardiac Surgery

Levosimendan and Mortality in Cardiac Surgery 711/235=4. 7% v 26/205=12. 7% 7 P=0. 007 7 NNT = 12

Levosimendan and Myocardial Infarction

Evidence! LEVOSIMENDAN VS CONTROL Myocardial Infarction in cardiac surgery 72/183=1. 1% v 9/153=5. 9% 7 P=0. 04

Levosimendan and Acute Renal Failure NNT = 6

LEVOSIMENDAN 2

ITACTA ONGOING RCTs TOPICS HOSPITALS PATIENTS GRANTS z VOLATILE ANESTHETICS z 4 200 AIFA 2006 z FENOLDOPAM z 34 1. 000 MINISTRY 2008 z DESMOPRESSIN z 3 200 3 10 3 200 1. 000 150 z z z ESMOLOL LEVOSIMENDAN VALVOLE PERCUTANEE landoni. giovanni@hsr. it www. itacta. org z z z

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

RESULTS Variables Fenoldopam N=40 ARF(25%Creatinine 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, days 3(1 -6) 3(1 -8. 5) 0. 9 Hospital stay, days 13(7 -19) 10. 5(6 -20. 5) 0. 8 increase), n(%) z Post-operative data Dopamine N=40 p

Am J Kidney Dis. 2007; 4956 -68. IF 4. 4

Fenoldopam and Death in Critically ill patients 81/487(17%) versus 109/531 (21%) p=0. 01 NNT=26

Pooled estimates of risk for need for renal replacement therapy 34/526 (6%) versus 59/570 (10%) p=0. 007 NNT=26

Fenoldopam and Death in Cardiovascular Surgery 28/503 (6%) versus 55/503 (11%) p=0. 002 NNT=19

Fenoldopam and renal replacement therapy in cardiovascular surgery 30/528 (6%) versus 71/531 (13%) p<0. 001 NNT=13

ITACTA ONGOING RCTs TOPICS HOSPITALS PATIENTS GRANTS z VOLATILE ANESTHETICS z 4 200 AIFA 2006 z FENOLDOPAM z 34 1. 000 MINISTRY 2008 z DESMOPRESSIN z 3 200 3 10 3 200 1. 000 150 z z z ESMOLOL LEVOSIMENDAN VALVOLE PERCUTANEE landoni. giovanni@hsr. it www. itacta. org z z z

FENOLDOPAM E INSUFFICIENZA RENALE FENO-HSR

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

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

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

DESFLURANE versus PROPOFOL (fentanyl-based cardiac anesthesia)

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

Peak TROPONIN I ng/ml OFF-PUMP CABG ON-PUMP CABG MITRAL SURGERY 1. 2 (0. 9 -1. 9) versus 2. 7 (2. 1 -4. 0) 2. 5 (1. 1 -5. 3) versus 5. 5 (2. 3 -9. 5) 11. 0 (7. 5 -17. 4) versus 11. 5 (6. 9 -18. 8) *P<0. 001 P=0. 7

Troponin I after OFF-PUMP CABG

Troponin I after CABG (CPB)

Troponin I after MITRAL SURGERY

Volatile Anesthetics

META-ANALYSIS (cardiac anaesthesia) 4 22 randomized studies (15 CPB-CABG; 6 OP-CABG; 1 mitral valve surgery) 4 1922 patients (904 TIVA and 1018 DES or SEVO) 4 16 studies administered volatile anesthetics throughout all the procedure (6 studies for 5 -30 minutes)

Evidence! Mortality

Evidence! Mortality 74/977=0. 4% v 14/872=1. 6% 7 NNT=84 7 RRR=(1, 6 -0, 4)/1, 6=75% 7 OR: 0. 31(0. 12 -0. 80) 7 P=0. 02

Evidence! Myocardial infarction

Evidence! Myocardial infarction 724/979=2. 4% v 45/874=5. 1% 7 NNT=37 7 RRR: (5. 1 -2. 4)/5. 1 = 53% 7 OR: 0. 51(0. 32 -0. 84) 7 p=0. 008

RISK-ADJUSTED MORTALITY (%) 8 P=0. 022 6 4 2 0 NO USE ONLY INCISION/ STERNOTOMY PART OF THE OPERATION ALL OF THE OPERATION DURATION OF USE OF INHALATORY ANESTHETICS DURING SURGERY

RISK-ADJUSTED MORTALITY (%) 8 P=0. 007 6 4 2 0 0% TO <50% OF CASES ≥ 50% OF CASES USE OF INHALATORY ANESTHETICS

NON-CARDIAC SURGERY

Cardioprotection & anaesthesia Volatile Anesthetics C b blockers “recommended” C Statins “suggested” in selected pts C a 2 agonists “may be considered” in selected pts C Ca++ antagonists “may be considered” in selected pts C Insulin “reasonable” in hyperglycaemic pts C Volatile Anesthetics “can be beneficial”

Every 1. 000 patients receiving extended release METOPROLOL z PREVENTION OF 15 MYOCARDIAL INFARCTON z PREVENTION OF 3 CABG z PREVENTION OF 7 ATRIAL FIBRILLATION

Every 1. 000 patients receiving extended release METOPROLOL z EXCESS OF 8 DEATHS z EXCESS OF 5 STROKE z EXCESS 53 HYPOTENSION z EXCESS 42 BRADICARDIA

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

Evidence? A meta-analysis in noncardiac surgery Total 79 Anesth analg 20 BJA 14 EJA 11 Acta anaesthesiol scand 8 Anaesthesia 5 J Anesth 4 Anesthesiology 3 Minerva anestesiol 2 Altri 13

Evidence? A meta-analysis in noncardiac surgery 4 400 authors 4 240 reviewers 4 90 editors 0 deaths 0 myocardial infarctions

TAKE HOME MESSAGE z MAGIC BULLET z NNT TO PREVENT ONE DEATH z PEXELIZUMAB z LEVOSIMENDAN z FENOLDOPAM z VOLATILE AGENTS z 100 z 12 z 19 or 26 z 84

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

ITACTA ONGOING RCTs TOPICS HOSPITALS PATIENTS GRANTS z VOLATILE ANESTHETICS z 4 200 AIFA 2006 z FENOLDOPAM z 34 1. 000 MINISTRY 2008 z DESMOPRESSIN z 3 200 3 10 3 200 1. 000 150 z z z ESMOLOL LEVOSIMENDAN VALVOLE PERCUTANEE landoni. giovanni@hsr. it www. itacta. org z z z

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 z 1. Sostituzioni valvolari percutanee (covello. remodaniel@hsr. it) z 2. Monitoraggio emodinamico mini-invasivo (giuliamaj@hotmail. com) z 3. Statistica in anestesia e terapia intensiva (monaco. fabrizio@hsr. it) z 4. Analgesia selettiva in chirurgia toracica (drpiraccini@gmail. com)

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