IRCCS Ospedale San Raffaele Milano Universit VitaSalute San

IRCCS Ospedale San Raffaele Milano Università Vita-Salute San Raffaele Peri-operative cardiac protection Relatore: Dott. Giovanni Landoni Tutorial in General Anesthesia, Milano, 28 Marzo 2009

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

REDUCING PERIOPERATIVE MYOCARDIAL INFARCTION z EPIDURAL ANESTHESIA (non-cardiac surgery) z BETA BLOCKERS (non-cardiac surgery) ? ? !! z VOLATILE AGENTS (cardiac surgery) z LEVOSIMENDAN (cardiac surgery)

REDUCING PERIOPERATIVE MORTALITY AND MYOCARDIAL INFARCTION z VOLATILE AGENTS (cardiac surgery) z LEVOSIMENDAN (cardiac surgery)

REDUCING PERIOPERATIVE MORTALITY z FENOLDOPAM z PEXELIZUMAB (cardiac surgery) z DOPEXAMINE z EARLY ENTERAL NUTRITION (intestinal surgery) z INSULINE !!? ? z STATINS

Anaesthesia and Outcome Volatile Anesthetics Could VOLATILE anaesthetics influence outcome? Could VOLATILE anaesthetics have non-anaesthetic properties?

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

INOTROPES in ICU OFF-PUMP CABG ON-PUMP CABG MITRAL SURGERY 35. 1% versus 56. 4% 32. 0% versus 41. 3% 42. 4% versus 54. 1% *P=0. 04 P=0. 3

NEW Q WAVES OFF-PUMP CABG ON-PUMP CABG MITRAL SURGERY 11% versus 17% 6. 7% versus 18. 7% 1. 7% Versus 1. 6% P=0. 8 *P=0. 049 P=0. 7

Evidence? I II IV V VI Meta-analysis and/or large randomized studies Randomized trials Non-randomized prospective trials Retrospective studies Case reports and Expert Opinion Animal / Laboratories Studies

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

Mortality NNT=84 Treat 84 to save one

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

Myocardial infarction NNT=37 Treat 37 to save one

Evidence! PEAK CARDIAC TROPONIN I WMD -2. 35 ng/d. L [-3. 09, -1. 60], p<0. 00001

Evidence! INOTROPE USE IN ICU OR 0. 47 [0. 29, 0. 76], p < 0. 002

Evidence! Mechanical ventilation WMD -0. 49 hours [-0. 97, -0. 02], p = 0. 4

Evidence! ICU STAY WMD -7. 10 hours [-11. 47, -2. 73], p < 0. 001

Evidence! HOSPITAL STAY WMD -2. 26 days [-3. 83, -0. 68], p = 0. 005

Name of the Hospital % mortality at 30 days CLINICA SAN ROCCO - BRESCIA 0, 26% OSPEDALE SAN RAFFAELE MILANO 0, 36% PRESIDIO OSPEDALIERO "C. POMA" MANTOVA 0, 48% OSPEDALE CIVILE LEGNANO - MI 0, 67% OSPEDALE SANTA CROCE E CARLE CUNEO 1, 15% OSPEDALE S. CHIARA TRENTO 1, 16% NUOVO POLO CARDIOLOGICO - TRIESTE 1, 22% HESPARIA HOSPITAL S. R. L. MODENA 1, 32%

Conclusions: Volatile Anesthetics in cardiac surgery Volatile Anesthetics Sevoflurane&Desflurane: ↓post cardiac surgery mortality Direct and indirect protection Desflurane in CABG surgery: • ↓postoperative c. Tn. I release • ↓postoperative inotropic support • ↓hospitalization +/cardiopulmonary bypass

Have we forgotten about noncardiac surgery?

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

Evidence? A meta-analysis in noncardiac surgery 4281 citations retrieved from database searches 3936 titles/abstracts excluded because non-relevant 344 studies assessed according to the selection criteria 79 Randomised Controlled Trials finally included in the systematic review 265 studies excluded according to explicit exclusion criteria 35 duplicate reports 51 no TIVA group 75 cardiac surgery 46 retrospective 25 non randomised 21 paediatric 12 not available

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

Have we forgotten about CARDIAC MORBIDITY and MORTALITY in noncardiac surgery?

WHAT’S NEXT

SEVOFLURANE IN STENTING PROCEDURES: A RANDOMIZED CONTROLLED STUDY. METHODS 30 patients 20’ 16 SEVOFLURANE 0, 5 MAC + oxygen/air 14 Oxygen/air PTCA+stenting Endpoint primario: Tn. I postprocedurale

SEVOFLURANE IN STENTING PROCEDURES: A RANDOMIZED CONTROLLED STUDY. RESULTS SEVOFLURANE PLACEBO Tn. I, median (25°-75° percentile) vs 0. 15 (0 -4. 73) ng/dl 0. 14 (0 -0. 87) ng/dl P = 0, 4 Landoni et al. JCVA 2008

Take home message 4 RCTs should confirm the promising results of volatile anesthetics in noncardiac surgery 4 Cardiac Troponin I could be an excellent intermediate (surrogate? ) outcome in cardiac and non-cardiac high risk surgical patients

Cardioprotection & anaesthesia Epidural analgesia

CLINICAL IMPLICATIONS AND RISKS The risk of epidural haematoma or other serious complications ( before systemic heparitation) is 1: 4500 Ruppen W et al, BMC Anesthesiol. 2006; 6: 10 No epidural haematoma has ever been described in a randomized setting Two case reports have been recently published Sharma S et al, J Cardiothorac Vasc Anesth. 2004; 18: 759762 Rosen DA et al, Anesth Analg 2004; 98: 966 -969

Epidural analgesia Our response to the issues: A meta-analysis of 33 trials randomized 2366 patients ( 1231 receiving general anaesthesia and 1135 receiving epidural anaesthesia)

Epidural analgesia Results 1 EPIDURAL ANESTHESIA REDUCES THE RISK OF PERIOPERATIVE MYOCARDIAL INFARCTION 15/987 ( 1. 5%) vs 30/1109 (2. 7%) OR= 0. 53 (0. 29 -0. 97) P for effect = 0. 04 P for heterogeneity = 0. 56 Number to treat (NNT) = 84

Epidural analgesia Results 2 EPIDURAL ANESTHESIA REDUCES THE RISK OF ACUTE RENAL FAILURE 8/426 ( 1. 9%) vs 21/440 (4. 8%) OR= 0. 43 P for effect = 0. 03 P for heterogeneity = 0. 8 Number to treat (NNT) = 35

Epidural analgesia Results 3 EPIDURAL ANESTHESIA REDUCES THE TIME OF MECHANICAL VENTILATION P for effect < 0. 001 P for heterogeneity <0. 001

Epidural analgesia Results 4 MORTALITY 8/975 ( 0. 8%) vs 12/1071 (1. 1%) OR = 0. 69 P for effect = 0. 4 P for heterogeneity = 0. 4

Epidural analgesia Conclusions THIS IS THE FIRST TIME THAT LOCOREGIONAL ANAESTHESIA IS SHOWN TO HAVE AN IMPACT ON CLINICALLY RELEVANT ENDPOINTS FOLLOWING CARDIAC SURGERY This analysis suggests that epidural analgesia reduces perioperative myocardial infarction in low risk patients undergoing cardiac surgery While awaiting the results of large randomized controlled studies in high risk patients

NT-pro. BNP in the 46 patients with epidural anaesthesia (median, interquartile and range values in a logarithmic scale) compared to the 46 patients who received standard general anaesthesia

β-blockers and Non-cardiac surgery Pro β blockers “recommended” Pro Cons

β-blockers and Non-cardiac surgery Cons: POISE trial Pro Cons

β-blockers and Non-cardiac surgery CONS. . Perioperative βblock was associated to increased mortality following stroke

β-blockers and Cardiac surgery “Interventions for preventing post-operative atrial fibrillation in patients undergoing heart surgery” E Crystal, MS Garfinkle, SS Connolly, TT Ginger, K Sleik, SS Yusuf Cochrane Database of Systematic Reviews 2004 in Issue 4, 2004 . . the lack of evidence for a possible negative inotropic effect has limited the use of β block in cardiac surgery.

β-blockers: Our reviews on esmolol RIDUZIONE ISCHEMIA Ischemia 5/55 (9%) 12/ 51 (23%) 0. 01

β-blockers: Our reviews on esmolol ESMOLOLO IN NON CARDIOCHIRURGIA • Non riportata mortalità ed infarto nei due gruppi (34 studi, 1739 pazienti) Esmololo Morte Infarto Controllo P value

β-blockers: Our reviews on esmolol ESMOLOL IN CARDIAC SURGERY. A META-ANALYSIS OF RANDOMISED CONTROLLED STUDIES JCVA 2009, IN PRESS

β-blockers: Our reviews on esmolol ▪ 23 studies ▪ 979 patients ▪ All mono-center studies ▪ Analysis with Review Manager 4. 2 ▪ We tried to contact all the corresponding authors to know if they had new data

β-blockers: Our reviews on esmolol Non differenze per mortalità ed infarto

β-blockers: Our reviews on esmolol RIDUZIONE ISCHEMIA Ischemia 15/122 (12%) 36/140 (27%) 0. 009

β-blockers: Our reviews on esmolol RIDUZIONE INOTROPI Inotropi 29/153 (18%) 48/146 (32%) 0. 002

ESMOLOLO IN CEC Studio randomizzato 200 pazienti (100 esmololo-100 placebo) DTD>60%, FE< 50% Bolo esmololo in CEC (circa 3 mg/kg durante cardioplegia) Incidenza di FV in uscita CEC Valutazione danno miocardico, degenza

Evidence! LEVOSIMENDAN VS CONTROL Mortality in cardiac surgery 711/235=4. 7% v 26/205=12. 7% 7 P=0. 007

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

“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)

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