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Cardiac Protection byVolatile Anesthetics

Giovanni Landoni, MD

Head of Research

Dept. of Anaesthesiology & Intensive CareVita-Salute University of Milan, Italy

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Introduction

Desurane and sevourane are the only anesthetic

drugs that have been proven to reduce perioperativemorbidity and mortality up to date.1

A recent meta-analysis has shown a reduction in

perioperative myocardial inarction (MI) and death

in those patients randomized to receive desurane or

sevourane versus a total intravenous anesthesia (TIVA)

or cardiac surgery.1

The most recent American College o Cardiology/

American Heart Association Guidelines recommend the

use o volatile anesthetic agents during non-cardiac surgery

or the maintenance o general anesthesia in patients at

risk or MI.2

The mechanisms that lie beneath the protection rom

perioperative cardiac ischaemic damage given by desurane

and sevourane still lack a complete explanation, although

pharmacological properties which are not related to

anesthetic or haemodynamic eects o these drugs appear

to be involved.

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Clinical Evidence in Cardiac Surgery

An extensive search in BioMed Central and PubMed,the scanning o reerences o retrieved articles andpertinent reviews and contacts with international experts

lead to the identifcation o 22 randomized clinical

trials that compared a TIVA versus an anesthesia plan,

including administration o desurane or sevourane,

perormed on cardiac surgical patients with no restrictionin dose and time o administration.

The primary end-point o the present review was the

rate o in-hospital MI as per author defnition while the

co-primary end-point was the rate o hospital mortality.

Other relevant secondary end-points were: peak cardiac

troponin (cTn) release, inotrope use, time on mechanicalventilation, intensive care unit (ICU) and hospital stay

(LOS), and cardiac events (at the longest ollow-up

available or each study).

Computations were perormed with SPSS 11.0 (SPSS,

Chicago, IL, USA), and RevMan 4.2 (a reeware

available rom The Cochrane Collaboration). (40)

The 22 included trials randomized 1,922 patients (904

to TIVA and 1,018 receiving desurane or sevourane

in their anesthesia plans). Most studies were perormed

on patients undergoing on-pump coronary artery bypass

grating (CABG), six on patients undergoing o-pump

CABG, and only one investigated patients undergoing

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mitral surgery. Most authors administered volatile anesthetics

throughout all the procedures while six authors administered the

volatile anesthetics or a short time (5 to 30 minutes) and only

beore or during the expected cardiac damage.

Volatile anesthetics dosage varied across studies, being always

>0.15 MAC and ranging 0.15-2 MAC in the 475 patients

receiving desurane, and 0.25-4 MAC in the 543 patients

receiving sevourane. Three studies (26) (30) (37) were multi-

centric, while the rest had a single-center design.

Overall analysis showed that, in comparison to TIVA, volatileanesthetics were associated with signifcant reductions in the

rates o all major endpoints. Specifcally, volatile anesthetics

reduced the risk o MI (24/979 [2.4%] in the volatile anesthetics

group vs. 45/874 [5.1%] in the control arm, OR=0.52 [0.32-

0.84], p or eect=0.008, p or heterogeneity=0.77, I2=0%)

(Figure 1), and all-cause mortality (4/977 [0.4%] vs. 14/872

[1.6%], OR=0.31 [0.12-0.80], p or eect=0.02, p or

heterogeneity=0.88, I2=0%) (Figure 2). Beside increasing in-

hospital survival, use o volatile anesthetics was also associated

with a signifcant reduction in cTnI peak release (WMD 2.35

ng/dl [-3.09,-1.60], p or eect

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Figure 1

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Figure 2

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Recent American College o Cardiology/AmericanHeart Association Guidelines recommended volatileanesthetic agents during non-cardiac surgery or the

maintenance o general anesthesia in patients at risk or

MI (class IIa, level o Evidence B), but whether these

cardioprotective properties exist in non-cardiac surgery

settings is controversial.

A recent meta-analysis3 included 79 studies, involving

6,219 patients (2,768 received TIVA and 3,451 received

desurane or sevourane in their anesthesia plans)

undergoing non-cardiac surgery. Inclusion criteria were

random allocation to treatment, comparison o a TIVA

regimen vs. an anesthesia plan including desurane orsevourane, perormed on adult, and non-cardiosurgical

patients. All authors administered volatile or intravenous

anesthetics throughout the procedure. Volatile anesthetic

dosage varied across studies, ranging 0.33-2 MAC in the

609 patients receiving desurane and 0.25-2 MAC in the

2,842 patients receiving sevourane. No MI or deaths

were observed in any o the examined studies. No author

reported any postoperative MI or death among the study

population, nor any signifcant cardiac adverse event.

Up to date no randomized study, among those which

compared halogenated to intravenous anesthetics, has

addressed major outcomes such as MI or mortality.

Clinical Evidence inNon-Cardiac Surgery

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H

alogenated agents mimic ischaemic

preconditioning, a powerul cardioprotective

phenomenon frst described in 19864, which represents

an adaptive response to brie sublethal episodes o

ischaemia leading to a pronounced protection against

subsequent lethal ischaemia. Application o ischaemic

preconditioning (IPC) in patients is not easible because

an ischaemic episode may reduce cardiac reserve and

exacerbate symptoms.

The potential cardiac protective eects o volatile

anesthetics were actually discovered beore the concept

o anesthetic preconditioning had been investigated. In

1988, Warltier et al.5 demonstrated that pretreatment

with halothane or isourane improved let ventricular

systolic unction ater a 15-minute let anterior

descending coronary artery (LAD) occlusion. Nine

years later, Cason et al.6 showed that a short exposure

to isourane prior to ischaemia triggers a signal that

protects the myocardium, thus introducing the concept

o anesthetic preconditioning. Since then, a wealth

o data regarding cardiac protection by anestheticshas been produced, and well-designed animal studies

have repeatedly demonstrated that exposure o the

myocardium to a volatile anesthetic beore a period o

ischaemia signifcantly protects the myocardium against

subsequent ischaemia-reperusion injury with better

recovery o contractile unction ater ischaemia and

reduced inarct size.

Mechanism o Action

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Anesthetic preconditioning appears to be based on a dose-

dependent signal: the degree o protection is related to the

concentration o drug administered and to the duration o

the administration itsel. Furthermore, it is not dependent on

ischaemic preconditioning and does not require

pre-emptive ischaemia.

Two windows o protection have been described: an early(or

classical) preconditioning (PC), lasting around one or two hours,

and a latepreconditioning, reappearing ater 24 hours and

lasting up to 72 hours. Although early and late preconditioning

share many eatures, the latter ollowing the frst, they probably

involve dierent signalling pathways which have not been

ully understood yet. ATP-dependent potassium channels on

mitochondrial membranes, reactive oxygen species, the apoptotic

cascade, nitric oxide, and calcium intracellular overload all

appear to play a role in preconditioning. Volatile anesthetics also

reduce neutrophil and platelet adhesion to the vascular wall aterischaemia.

Only recently has research turned to clinical implementation

o preconditioning protocols, and anesthetic preconditioning

(APC) has indeed been demonstrated in randomized clinical

trials conducted in patients undergoing cardiac surgery

mostly coronary artery bypass grat. Myocardial ischemia is anintegral part o this type o surgery, allowing transposition o a

preconditioning/ischaemia/reperusion sequence into a clinical

protocol. The frst clinical study using a preconditioning protocol

with an anesthetic agent was published in 19997 and showed

that administration o isourane prior to aortic cross-clamping

resulted in smaller postoperative release o creatine kinase MB(CK-MB) and cTn. Julier et al., in 20038, were the frst to

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demonstrate that translocation o PKC d and e isoorms one

o the mechanisms implicated as a pivotal step in anesthetic

preconditioning occurred in the human myocardium in

response to sevourane. Reduction in postoperative dismissal

o cardiac damage markers has been confrmed by many

subsequent studies. 912

A key question is whether the cardioprotective eects o

volatile anesthetics are clinically applicable and associated

with improved cardiac unction, ultimately resulting in a

better outcome in patients with coronary artery disease. This

is especially o interest since it was commonly believed that

the choice o the primary anesthetic agent does not result in a

dierent outcome13. The frst study to suggest that the use o

halogenated anesthetics might have relevant clinical advantages

was conducted in 200212. It appeared rom this study that

the use o sevourane was associated with a preservation o

global haemodynamic and let ventricular unction, with asignifcant lower postoperative release o cTnI compared with

the TIVA regimen. Two recent RCTs confrmed these protective

properties in terms o cTnI release, and also demonstrated

that the use o desurane during coronary surgery is associated

with shorter ICU and overall LOS, and a aster weaning rom

mechanical ventilation.

9, 10

De Hert et al. also showed that the cardioprotective eects

(lower postoperative cTnI release and preservation o

postoperative cardiac unction) o an anesthetic regimen

with sevourane are most apparent when the volatile

anesthetic is administered throughout the entire surgical

procedure, as compared to administration only beore or atercardiopulmonary bypass (CPB)11. Murphyet al. showed how

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the choice o morphine instead o entanyl may allow an APC protocol to

yield a better cardiac unction ollowing CABG14. These data support the

idea that the cardioprotective eects o anesthetic agents depend upon an

interaction o actors such as the administration protocols, the choice o a

specifc agent, the concomitant use o other drugs, and the variables used

to assess myocardial unction15.

Only one, very recent RCT has studied anesthetic preconditioning

in mitral valve surgery16. The authors ound no advantage in terms

postoperative cTnI dismissal in the overall population but demonstrated

a signifcant reduction in those patients with concomitant coronary

artery disease.

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Conclusions

This is the frst time that the choice o an anesthetic

regimen was shown to have an impact on patientsoutcomes ollowing cardiac surgery1. Interestingly,

the only authors who compared dierent timings o

sevourane administration ound that the maximum

protection was yielded by administration throughout the

procedure, as compared to administration only beore,

during or ater cardiopulmonary bypass11.

Halogenated agents have non-anesthetic properties

that cause an endogenous adaptive response o

the myocardium to ischaemic insults. The cellular

mechanisms responsible or such protection are not

ully understood yet, but many studies have indirectly

evidenced that this preconditioning property indeed

translates into clinically evident cardiac protection in

patients undergoing CABG.

A recent meta-analysis1 has shown or the frst time that

the use o desurane and sevourane in an anesthetic plan

yields a better outcome, in terms o mortality and cardiac

morbidity, in patients undergoing cardiac surgery.

The most recent American College o Cardiology/

American Heart Association Guidelines recommend the

use volatile anesthetic agents during non-cardiac surgery

or the maintenance o general anesthesia in patients at

risk or MI2.

Editors Note: This review analyses the clinical evidence of volatile anesthetic

agents in comparison to total intravenous anesthesia in cardiac and

non-cardiac surgery. The studies included in this review dont analyse the

combined volatile anesthesia and intravenous approach.

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1. Landoni G, Biondi-Zoccai GG, Zangrillo A, Bignami E, DAvolio S,Marchetti C, et al. Desurane and sevourane in cardiac surgery: ameta-analysis o randomized clinical trials.J Cardiothorac Vasc Anesth2007;21(4):502-11.

2. Fleisher LA, Beckman JA, Brown KA, Calkins H, Chaiko E,Fleischmann KE, et al. ACC/AHA 2007 Guidelines on PerioperativeCardiovascular Evaluation and Care or Noncardiac Surgery: ExecutiveSummary. A Report o the American College o Cardiology/AmericanHeart Association Task Force on Practice Guidelines (Writing Committeeto Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluationor Noncardiac Surgery).J Am Coll Cardiol2007;50(17):1707-32.

3. Fochi O, Bignami E, Landoni G, Pappalardo F, Calabr MG, GiardinaG, et al. Cardiac protection by volatile anesthetics in non-cardiac surgery. Ameta-analysis.Minerva Anestesiol2007;73(10, Suppl 2):26 [abstr].

4. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia:a delay o lethal cell injury in ischemic myocardium. Circulation1986;74(5):1124-36.

5. Warltier DC, al-Wathiqui MH, Kampine JP, Schmeling WT.Recovery o contractile unction o stunned myocardium in chronicallyinstrumented dogs is enhanced by halothane or isourane.Anesthesiology

1988;69(4):552-65.6. Cason BA, Gamperl AK, Slocum RE, Hickey RF. Anesthetic-inducedpreconditioning: previous administration o isourane decreases myocardialinarct size in rabbits.Anesthesiology1997;87(5):1182-90.

7. Belhomme D, Peynet J, Louzy M, Launay JM, Kitakaze M, Menasche P.Evidence or preconditioning by isourane in coronary artery bypass gratsurgery. Circulation 1999;100(19 Suppl):II340-4.

8. Julier K, da Silva R, Garcia C, Bestmann L, Frascarolo P, Zollinger A,et al. Preconditioning by sevourane decreases biochemical markers or

myocardial and renal dysunction in coronary artery bypass grat surgery:a double-blinded, placebo-controlled, multicenter study.Anesthesiology2003;98(6):1315-27.

9. Tritapepe L, Landoni G, Guarracino F, Pompei F, Crivellari M,Maselli D, et al. Cardiac protection by volatile anesthetics: a multicentrerandomized controlled study in patients undergoing coronary artery bypassgrating with cardiopulmonary bypass. Eur J Anaesthesiol2007;24(4):323-31.

10. Guarracino F, Landoni G, Tritapepe L, Pompei F, Leoni A, Aletti G,et al. Myocardial damage prevented by volatile anesthetics: a multicenter

randomized controlled study.J Cardiothorac Vasc Anesth 2006;20(4):477-83.

Reerences

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11. De Hert SG, Van der Linden PJ, Cromheecke S, Meeus R, Nelis A, Van Reeth V, et al.Cardioprotective properties o sevourane in patients undergoing coronary surgery withcardiopulmonary bypass are related to the modalities o its administration.Anesthesiology2004;101(2):299-310.

12. De Hert SG, ten Broecke PW, Mertens E, Van Sommeren EW, De Blier IG, Stockman BA,et al. Sevourane but not propool preserves myocardial unction in coronary surgery patients.Anesthesiology2002;97(1):42-9.

13. Tuman KJ, McCarthy RJ, Spiess BD, DaValle M, Dabir R, Ivankovich AD. Does choiceo anesthetic agent signifcantly aect outcome ater coronary artery surgery?Anesthesiology1989;70(2):189-98.

14. Murphy GS, Szokol JW, Marymont JH, Avram MJ, Vender JS. Opioids andcardioprotection: the impact o morphine and entanyl on recovery o ventricular unction atercardiopulmonary bypass.J Cardiothorac Vasc Anesth 2006;20(4):493-502.

15. De Hert SG. Anesthetic preconditioning: how important is it in today's cardiac anesthesia?JCardiothorac Vasc Anesth 2006;20(4):473-6.

16. Landoni G, Calabr MG, Marchetti C, Bignami E, Scandroglio AM, Dedola E, et al.Pharmacological preconditioning in patients undergoing mitral surgery with or withoutconcomitant ischaemic disease.J Cardiothorac Vasc Anesth 2007, In press.

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