Pharmacological pre-emptive strategies for cardiac surgery : give me the magic bullet , please

Pharmacological pre-emptive Pharmacological pre-emptive strategies for cardiac strategies for cardiac surgery: give me the magic surgery: give me the magic bullet, pleasebullet, please

Speaker:Speaker: Landoni GLandoni G INTERCEPT 2009INTERCEPT 2009

S Donato Milanese, Milan, April 17h 2009S Donato Milanese, Milan, April 17h 2009

IRCCS Ospedale San Raffaele MilanoIRCCS Ospedale San Raffaele MilanoUniversità Vita-Salute San RaffaeleUniversità Vita-Salute San Raffaele

MAGIC BULLETS TO REDUCE MORTALITY IN CARDIAC SURGERY

THERE ARE NO GUIDELINES

THERE IS NO CONSENSUS CONFERENCE

THERE IS NO LARGE RANDOMIZED CONTROLLED STUDY ADEQUATELY POWERED TO SUGGEST A REDUCTION IN MORTALITY

AN OVERVIEW OF META-ANALYSIS

PEXELIZUMAB

LEVOSIMENDAN

FENOLDOPAM

VOLATILE AGENTS (Intercept 2006)

AN OVERVIEW OF META-ANALYSIS

MAGIC BULLET

PEXELIZUMABLEVOSIMENDANFENOLDOPAMVOLATILE AGENTS

NNT TO PREVENT ONE DEATH

1001219 or 2684

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 2005 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

Number of patients and interventions of included studies.

First author Time of administrationSetting

Bolus dose Continuous infusion dose Length of infusion

Al-Shawaf LCOS# 12 g/kg 0.1-0.2g/kg/min 24 hours

Alvarez 2005 LCOS# 12g/kg 0.2g/kg/min 24 hours

Alvarez 2006 LCOS# 12g/kg 0.2g/kg/min 24 hours

Barisin Before surgery 12/24g/kg

no no

De Hert 2007 After CPB† No bolus 0.1g/kg/min 19+4 hours

De Hert 2008 First group : after induction of anesthesiaSecond group : after CPB†

No bolus 0.1g/kg/min 22+4 hours in the first group, 23+3 hours in the second one

Husedzinovic Before surgery 12g/kg no no

Jarvela After induction No bolus 0.2g/kg/min 24 hours

Levin LCOS# 10g/kg 0.1g/kg/min 24 hours

Tritapepe Before CPB† 24g/kg no no

† CPB: cardiopulmonary bypass# LCOS: low cardiac output syndrome

Levosimendan and Mortality in Cardiac Surgery

Review: LEVOSIMENDAN CCH (12/1/2009)Comparison: 01 perioperative levosimendan Outcome: 02 Mortality

Study Levosimendan Control Peto OR Peto ORor sub-category n/N n/N 95% CI 95% CI

Al-Shawaf 1/14 1/16 1.15 [0.07, 19.41] Alvarez 2005 1/15 0/15 7.39 [0.15, 372.38] Alvarez 2006 1/25 1/25 1.00 [0.06, 16.45] Barisin 0/21 0/10 Not estimable De Hert 2007 0/15 3/15 0.12 [0.01, 1.22] De Hert 2008 1/40 4/20 0.11 [0.02, 0.72] Husedzinovic 0/12 0/12 Not estimable Jarvela 1/12 0/12 7.39 [0.15, 372.38] Levin 6/69 17/68 0.31 [0.13, 0.77] Tritapepe 0/12 0/12 Not estimable

Total (95% CI) 235 205 0.35 [0.18, 0.71]Total events: 11 (Levosimendan), 26 (Control)Test for heterogeneity: Chi² = 8.27, df = 6 (P = 0.22), I² = 27.4%Test for overall effect: Z = 2.95 (P = 0.003)

0.001 0.01 0.1 1 10 100 1000

Favours levosimendan Favours control

11/235=4.7% v 26/205=12.7% P=0.007 NNT = 12

Levosimendan and Mortality in Cardiac Surgery

Levosimendan and Myocardial Infarction

Review: LEVOSIMENDAN CCH (12/1/2009)Comparison: 01 perioperative levosimendan Outcome: 04 Myocardial infarction

Study Levosimendan Control OR (fixed) OR (fixed)or sub-category n/N n/N 95% CI 95% CI

Al-Shawaf 1/14 0/16 3.67 [0.14, 97.49] Barisin 0/21 1/10 0.15 [0.01, 3.96] De Hert 2007 0/15 0/15 Not estimable De Hert 2008 0/40 0/20 Not estimable Husedzinovic 0/12 0/12 Not estimable Levin 1/69 8/68 0.11 [0.01, 0.91] Tritapepe 0/12 0/12 Not estimable

Total (95% CI) 183 153 0.26 [0.07, 0.97]Total events: 2 (Levosimendan), 9 (Control)Test for heterogeneity: Chi² = 3.25, df = 2 (P = 0.20), I² = 38.5%Test for overall effect: Z = 2.01 (P = 0.04)

0.001 0.01 0.1 1 10 100 1000

Favours levosimendan Favours control

LEVOSIMENDAN VS CONTROLMyocardial Infarction in cardiac surgery

2/183=1.1% v 9/153=5.9% P=0.04

Evidence!

Levosimendan and Acute Renal FailureNNT = 6

Review: LEVOSIMENDAN CCH (12/1/2009)Comparison: 01 perioperative levosimendan Outcome: 05 Acute renal failure

Study Levosimendan Control OR (fixed) OR (fixed)or sub-category n/N n/N 95% CI 95% CI

Al-Shawaf 2/14 5/16 0.37 [0.06, 2.29] Alvarez 2005 1/15 0/15 3.21 [0.12, 85.20] Barisin 0/21 0/10 Not estimable Levin 5/69 21/68 0.17 [0.06, 0.50]

Total (95% CI) 119 109 0.26 [0.12, 0.60]Total events: 8 (Levosimendan), 26 (Control)Test for heterogeneity: Chi² = 2.95, df = 2 (P = 0.23), I² = 32.1%Test for overall effect: Z = 3.16 (P = 0.002)

0.001 0.01 0.1 1 10 100 1000

Favours levosimendan Favours control

LEVOSIMENDAN 2

ITACTA ONGOING RCTsTOPICS HOSPITALS PATIENTS GRANTS

VOLATILE ANESTHETICS

FENOLDOPAM

DESMOPRESSIN

ESMOLOL LEVOSIMENDAN VALVOLE PERCUTANEE

landoni.giovanni@hsr.itwww.itacta.org

4 200 AIFA 2006

34 1.000 MINISTRY 2008

3 200

3 200 10 1.000 3 150

AIM OF THE STUDY

To evaluate the renoprotective action of fenoldopam

in a selected high-risk group of patients

undergoing cardiac surgery

RESULTSVariables Fenoldopa

mN=40

DopamineN=40

p

ARF(25%Creatinine increase), n(%)

17(42.5%)

16(40.0%)

0.9

ARF(50% Creatinine increase), n(%)

10(25%) 10(25%) 0.8

Renal Replacement Therapy.,n(%)

4(10%) 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

Post-operative data

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 RCTsTOPICS HOSPITALS PATIENTS GRANTS

VOLATILE ANESTHETICS

FENOLDOPAM

DESMOPRESSIN

ESMOLOL LEVOSIMENDAN VALVOLE PERCUTANEE

landoni.giovanni@hsr.itwww.itacta.org

4 200 AIFA 2006

34 1.000 MINISTRY 2008

3 200

3 200 10 1.000 3 150

FENO-HSR

FENOLDOPAM E INSUFFICIENZA RENALE

• Fenoldopam vs placebo

• randomized

• double blind

• multicenter (32 centers, 1000 patients)

DESIGN

“R” (RIFLE) after cardiac surgeryWhich patients?

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%

DESFLURANEDESFLURANEversusversus

PROPOFOLPROPOFOL((fentanyl-based cardiac anesthesia)fentanyl-based cardiac anesthesia)

RCT(382 PATIENTS)

OFF-PUMP CABG(112 PATIENTS)

ON-PUMP CABG(150 PATIENTS)

MITRAL SURGERY(120 PATIENTS)

PeakTROPONIN 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

Troponin I after OFF-PUMP CABG

Troponin I after CABG (CPB)

volatile anaesthetics

total intravenous anaesthesia

p=0,7

p<0,001

p=0,03

0

1

2

3

4

5

6

7

8

9

10

preop 0 4 18time, hour

cTn

I,

ng/m

l

Troponin I after MITRAL SURGERY

total intravenous anaesthesia

volatile anaesthetics

p=0,4

p=0,7

p=0,8

p=0,9

0

2

4

6

8

10

12

14

16

18

preop ICU arrival 4 hours day I day I I

time, hour

cTnI,

ng/m

l

Volatile AnestheticsVolatile Anesthetics

META-ANALYSIS(cardiac anaesthesia)

22 randomized studies (15 CPB-CABG; 6 OP-CABG; 1 mitral valve surgery)

1922 patients (904 TIVA and 1018 DES or SEVO)

16 studies administered volatile anesthetics throughout all the procedure (6 studies for 5-30 minutes)

MortalityEvidence!

Mortality

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

Evidence!

Myocardial infarctionEvidence!

24/979=2.4% v 45/874=5.1% NNT=37 RRR: (5.1-2.4)/5.1 = 53% OR: 0.51(0.32-0.84) p=0.008

Myocardial infarctionEvidence!

DURATION OF USE OF INHALATORY ANESTHETICS

DURING SURGERY

RIS

K-A

DJU

STED

MO

RTA

LIT

Y (

%) 8

6

4

2

0

NO USEALL OF THE OPERATION

ONLY INCISION/

STERNOTOMY

PART OF THE

OPERATION

P=0.022

RIS

K-A

DJU

STED

MO

RTA

LIT

Y (

%)

P=0.007

8

6

4

2

0

USE OF INHALATORY ANESTHETICS

0% TO <50%

OF CASES

≥50% OF CASES

P=0.007

NON-CARDIAC SURGERY

Cardioprotection & anaesthesia

Volatile AnestheticsVolatile Anesthetics

blockers “recommended”

Statins “suggested” in selected pts

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”

Every 1.000 patients receiving extended release METOPROLOL

PREVENTION OF 15 MYOCARDIAL INFARCTON PREVENTION OF 3 CABG PREVENTION OF 7 ATRIAL FIBRILLATION

Every 1.000 patients receiving extended release METOPROLOL

EXCESS OF 8 DEATHS EXCESS OF 5 STROKE EXCESS 53 HYPOTENSION EXCESS 42 BRADICARDIA

A meta-analysis in noncardiac surgery

6219 patients

2842 sevoflurane609 desflurane

2768 propofol

Evidence?

Total 79

Anesth analg 20

BJA 14

EJA 11

Acta anaesthesiol scand 8

Anaesthesia 5

J Anesth 4

Anesthesiology3

Minerva anestesiol 2

Altri 13

Anesth analg

BJA

EJA

Acta anestesiol scand

Anaesthesia

J anesth

Anesthesiology

Minerva anestesiol

Altri

A meta-analysis in noncardiac surgery

Evidence?

400 authors 240 reviewers 90 editors

0 deaths

0 myocardial infarctions

A meta-analysis in noncardiac surgery

Evidence?

TAKE HOME MESSAGE

MAGIC BULLET

PEXELIZUMABLEVOSIMENDANFENOLDOPAMVOLATILE AGENTS

NNT TO PREVENT ONE DEATH

1001219 or 2684

“PERCHE’ NON SIAM POPOLOPERCHE’ SIAM DIVISI”

MAMELI

ITACTA ONGOING RCTsTOPICS HOSPITALS PATIENTS GRANTS

VOLATILE ANESTHETICS

FENOLDOPAM

DESMOPRESSIN

ESMOLOL LEVOSIMENDAN VALVOLE PERCUTANEE

landoni.giovanni@hsr.itwww.itacta.org

4 200 AIFA 2006

34 1.000 MINISTRY 2008

3 200

3 200 10 1.000 3 150

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

1. Sostituzioni valvolari percutanee (covello.remodaniel@hsr.it)

2. Monitoraggio emodinamico mini-invasivo (giuliamaj@hotmail.com)

3. Statistica in anestesia e terapia intensiva (monaco.fabrizio@hsr.it)

4. Analgesia selettiva in chirurgia toracica (

drpiraccini@gmail.com)

For further slides on these topics please feel free to visit the

metcardio.org website:

http://www.metcardio.org/slides.html