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Cardiac Protection by

Volatile Anesthetics
Giovanni Landoni, MD
Head of Research
Dept. of Anaesthesiology & Intensive Care
Vita-Salute University of Milan, Italy
Introduction

D esflurane and sevoflurane are the only anesthetic


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

A recent meta-analysis has shown a reduction in


perioperative myocardial infarction (MI) and death
in those patients randomized to receive desflurane or
sevoflurane versus a total intravenous anesthesia (TIVA)
for cardiac surgery.1

The most recent American College of Cardiology/


American Heart Association Guidelines recommend the
use of volatile anesthetic agents during non-cardiac surgery
for the maintenance of general anesthesia in patients at
risk for MI.2

The mechanisms that lie beneath the protection from


perioperative cardiac ischaemic damage given by desflurane
and sevoflurane still lack a complete explanation, although
pharmacological properties which are not related to
anesthetic or haemodynamic effects of these drugs appear
to be involved.
Clinical Evidence in Cardiac Surgery

A n extensive search in BioMed Central and PubMed,


the scanning of references of retrieved articles and
pertinent reviews and contacts with international experts
lead to the identification of 22 randomized clinical
trials that compared a TIVA versus an anesthesia plan,
including administration of desflurane or sevoflurane,
performed on cardiac surgical patients with no restriction
in dose and time of administration.

The primary end-point of the present review was the


rate of in-hospital MI as per author definition while the
co-primary end-point was the rate of hospital mortality.
Other relevant secondary end-points were: peak cardiac
troponin (cTn) release, inotrope use, time on mechanical
ventilation, intensive care unit (ICU) and hospital stay
(LOS), and cardiac events (at the longest follow-up
available for each study).

Computations were performed with SPSS 11.0 (SPSS,


Chicago, IL, USA), and RevMan 4.2 (a freeware
available from The Cochrane Collaboration). (40)

The 22 included trials randomized 1,922 patients (904


to TIVA and 1,018 receiving desflurane or sevoflurane
in their anesthesia plans). Most studies were performed
on patients undergoing on-pump coronary artery bypass
grafting (CABG), six on patients undergoing off-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 for a short time (5 to 30 minutes) and only
before 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 desflurane, and 0.25-4 MAC in the 543 patients
receiving sevoflurane. Three studies (26) (30) (37) were multi-
centric, while the rest had a single-center design.

Overall analysis showed that, in comparison to TIVA, volatile


anesthetics were associated with significant reductions in the
rates of all major endpoints. Specifically, volatile anesthetics
reduced the risk of 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 for effect=0.008, p for 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 for effect=0.02, p for
heterogeneity=0.88, I2=0%) (Figure 2). Beside increasing in-
hospital survival, use of volatile anesthetics was also associated
with a significant reduction in cTnI peak release (WMD –2.35
ng/dl [-3.09,-1.60], p for effect <0.00001, p for heterogeneity
<0.00001, I2=94.1% with 1,463 included patients), and need
for inotropic support (170/679 [25.0%] vs 203/562 [36.1%],
OR=0.47 [0.29, 0.76], p for effect <0.002, p for heterogeneity
=0.008, I2=53.1% with 1,241 included patients). Furthermore,
the use of desflurane and sevoflurane was associated with shorter
ICU stay (WMD=-7.10 hours [-11.47; -2.73], p for effect
<0.001, p for heterogeneity <0.00001, I2=76.6% with 1,433
included patients), time to hospital discharge (WMD=-2.26
days [-3.83; -0.68], p for effect=0.005, p for heterogeneity

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Figure 1

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Figure 2

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<0.00001, I2=93.7% with 1,593 included patients), and time
on mechanical ventilation (WMD=-0.49 hours [-0.97; -0.02], p
for effect =0.04, p for heterogeneity 0.03, I2=44.1% with 1,846
included patients). Finally, only two studies reported one-year,
follow-up data concerning major cardiac events (defined as
cardiac death, nonfatal MI, unstable angina, intercurrent coronary
angioplasty, coronary artery bypass grafting, arrhythmias requiring
hospitalization and new episodes of congestive heart failure): 4/48
[8.3%] in the volatile anesthetics group vs. 11/45 [24.4%] in
the control arm, OR=0.23 [0.06-0.88], p for effect=0.03, p for
heterogeneity=0.47, I2=0%.

We assessed the robustness and applicability of our findings


through a series of sensitivity analyses, i.e. excluding one study
at a time, switching from fixed-effect to random-effect models,
and computing relative risks as well as risk differences. All sub-
analyses performed excluding one RCT at a time remained in the
same direction and magnitude of benefit in support of volatile
anesthetics as the overall analysis for MI and death.

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Clinical Evidence in
Non-Cardiac Surgery

R ecent American College of Cardiology/American


Heart Association Guidelines recommended volatile
anesthetic agents during non-cardiac surgery for the
maintenance of general anesthesia in patients at risk for
MI (class IIa, level of 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
desflurane or sevoflurane in their anesthesia plans)
undergoing non-cardiac surgery. Inclusion criteria were
random allocation to treatment, comparison of a TIVA
regimen vs. an anesthesia plan including desflurane or
sevoflurane, performed 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 desflurane and 0.25-2 MAC in the
2,842 patients receiving sevoflurane. No MI or deaths
were observed in any of the examined studies. No author
reported any postoperative MI or death among the study
population, nor any significant 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.

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Mechanism of Action

H alogenated agents mimic ischaemic


preconditioning, a powerful cardioprotective
phenomenon first described in 19864, which represents
an adaptive response to brief sublethal episodes of
ischaemia leading to a pronounced protection against
subsequent lethal ischaemia. Application of ischaemic
preconditioning (IPC) in patients is not feasible because
an ischaemic episode may reduce cardiac reserve and
exacerbate symptoms.

The potential cardiac protective effects of volatile


anesthetics were actually discovered before the concept
of anesthetic preconditioning had been investigated. In
1988, Warltier et al.5 demonstrated that pretreatment
with halothane or isoflurane improved left ventricular
systolic function after a 15-minute left anterior
descending coronary artery (LAD) occlusion. Nine
years later, Cason et al.6 showed that a short exposure
to isoflurane prior to ischaemia triggers a signal that
protects the myocardium, thus introducing the concept
of anesthetic preconditioning. Since then, a wealth
of data regarding cardiac protection by anesthetics
has been produced, and well-designed animal studies
have repeatedly demonstrated that exposure of the
myocardium to a volatile anesthetic before a period of
ischaemia significantly protects the myocardium against
subsequent ischaemia-reperfusion injury with better
recovery of contractile function after ischaemia and
reduced infarct size.

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Anesthetic preconditioning appears to be based on a dose-
dependent signal: the degree of protection is related to the
concentration of drug administered and to the duration of
the administration itself. Furthermore, it is not dependent on
ischaemic preconditioning and does not require
pre-emptive ischaemia.

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


classical) preconditioning (PC), lasting around one or two hours,
and a late preconditioning, reappearing after 24 hours and
lasting up to 72 hours. Although early and late preconditioning
share many features, the latter following the first, they probably
involve different signalling pathways which have not been
fully 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 after
ischaemia.

Only recently has research turned to clinical implementation


of preconditioning protocols, and anesthetic preconditioning
(APC) has indeed been demonstrated in randomized clinical
trials conducted in patients undergoing cardiac surgery —
mostly coronary artery bypass graft. Myocardial ischemia is an
integral part of this type of surgery, allowing transposition of a
preconditioning/ischaemia/reperfusion sequence into a clinical
protocol. The first clinical study using a preconditioning protocol
with an anesthetic agent was published in 19997 and showed
that administration of isoflurane prior to aortic cross-clamping
resulted in smaller postoperative release of creatine kinase MB
(CK-MB) and cTn. Julier et al., in 20038, were the first to

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demonstrate that translocation of PKC d and e isoforms — one
of the mechanisms implicated as a pivotal step in anesthetic
preconditioning — occurred in the human myocardium in
response to sevoflurane. Reduction in postoperative dismissal
of cardiac damage markers has been confirmed by many
subsequent studies. 9–12

A key question is whether the cardioprotective effects of


volatile anesthetics are clinically applicable and associated
with improved cardiac function, ultimately resulting in a
better outcome in patients with coronary artery disease. This
is especially of interest since it was commonly believed that
the choice of the primary anesthetic agent does not result in a
different outcome13. The first study to suggest that the use of
halogenated anesthetics might have relevant clinical advantages
was conducted in 200212. It appeared from this study that
the use of sevoflurane was associated with a preservation of
global haemodynamic and left ventricular function, with a
significant lower postoperative release of cTnI compared with
the TIVA regimen. Two recent RCTs confirmed these protective
properties in terms of cTnI release, and also demonstrated
that the use of desflurane during coronary surgery is associated
with shorter ICU and overall LOS, and a faster weaning from
mechanical ventilation.9, 10

De Hert et al. also showed that the cardioprotective effects


(lower postoperative cTnI release and preservation of
postoperative cardiac function) of an anesthetic regimen
with sevoflurane are most apparent when the volatile
anesthetic is administered throughout the entire surgical
procedure, as compared to administration only before or after
cardiopulmonary bypass (CPB)11. Murphy et al. showed how

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the choice of morphine instead of fentanyl may allow an APC protocol to
yield a better cardiac function following CABG14. These data support the
idea that the cardioprotective effects of anesthetic agents depend upon an
interaction of factors such as the administration protocols, the choice of a
specific agent, the concomitant use of other drugs, and the variables used
to assess myocardial function15.

Only one, very recent RCT has studied anesthetic preconditioning


in mitral valve surgery16. The authors found no advantage in terms
postoperative cTnI dismissal in the overall population but demonstrated
a significant reduction in those patients with concomitant coronary
artery disease.

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Conclusions

T his is the first time that the choice of an anesthetic


regimen was shown to have an impact on patients’
outcomes following cardiac surgery1. Interestingly,
the only authors who compared different timings of
sevoflurane administration found that the maximum
protection was yielded by administration throughout the
procedure, as compared to administration only before,
during or after cardiopulmonary bypass11.

Halogenated agents have non-anesthetic properties


that cause an endogenous adaptive response of
the myocardium to ischaemic insults. The cellular
mechanisms responsible for such protection are not
fully 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 for the first time that
the use of desflurane and sevoflurane in an anesthetic plan
yields a better outcome, in terms of mortality and cardiac
morbidity, in patients undergoing cardiac surgery.
The most recent American College of Cardiology/
American Heart Association Guidelines recommend the
use volatile anesthetic agents during non-cardiac surgery
for the maintenance of general anesthesia in patients at
risk for MI2.
Editor’s 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 don’t analyse the
combined volatile anesthesia and intravenous approach.

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References

1. Landoni G, Biondi-Zoccai GG, Zangrillo A, Bignami E, D’Avolio S,


Marchetti C, et al. Desflurane and sevoflurane in cardiac surgery: a
meta-analysis of randomized clinical trials. J Cardiothorac Vasc Anesth
2007;21(4):502-11.
2. Fleisher LA, Beckman JA, Brown KA, Calkins H, Chaikof E,
Fleischmann KE, et al. ACC/AHA 2007 Guidelines on Perioperative
Cardiovascular Evaluation and Care for Noncardiac Surgery: Executive
Summary. A Report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines (Writing Committee
to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation
for Noncardiac Surgery). J Am Coll Cardiol 2007;50(17):1707-32.
3. Fochi O, Bignami E, Landoni G, Pappalardo F, Calabrò MG, Giardina
G, et al. Cardiac protection by volatile anesthetics in non-cardiac surgery. A
meta-analysis. Minerva Anestesiol 2007;73(10, Suppl 2):26 [abstr].
4. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia:
a delay of lethal cell injury in ischemic myocardium. Circulation
1986;74(5):1124-36.
5. Warltier DC, al-Wathiqui MH, Kampine JP, Schmeling WT.
Recovery of contractile function of stunned myocardium in chronically
instrumented dogs is enhanced by halothane or isoflurane. Anesthesiology
1988;69(4):552-65.
6. Cason BA, Gamperl AK, Slocum RE, Hickey RF. Anesthetic-induced
preconditioning: previous administration of isoflurane decreases myocardial
infarct size in rabbits. Anesthesiology 1997;87(5):1182-90.
7. Belhomme D, Peynet J, Louzy M, Launay JM, Kitakaze M, Menasche P.
Evidence for preconditioning by isoflurane in coronary artery bypass graft
surgery. 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 sevoflurane decreases biochemical markers for
myocardial and renal dysfunction in coronary artery bypass graft surgery:
a double-blinded, placebo-controlled, multicenter study. Anesthesiology
2003;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 multicentre
randomized controlled study in patients undergoing coronary artery bypass
grafting with cardiopulmonary bypass. Eur J Anaesthesiol 2007;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.

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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 of sevoflurane in patients undergoing coronary surgery with
cardiopulmonary bypass are related to the modalities of its administration. Anesthesiology
2004;101(2):299-310.
12. De Hert SG, ten Broecke PW, Mertens E, Van Sommeren EW, De Blier IG, Stockman BA,
et al. Sevoflurane but not propofol preserves myocardial function in coronary surgery patients.
Anesthesiology 2002;97(1):42-9.
13. Tuman KJ, McCarthy RJ, Spiess BD, DaValle M, Dabir R, Ivankovich AD. Does choice
of anesthetic agent significantly affect outcome after coronary artery surgery? Anesthesiology
1989;70(2):189-98.
14. Murphy GS, Szokol JW, Marymont JH, Avram MJ, Vender JS. Opioids and
cardioprotection: the impact of morphine and fentanyl on recovery of ventricular function after
cardiopulmonary 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? J
Cardiothorac Vasc Anesth 2006;20(4):473-6.
16. Landoni G, Calabrò MG, Marchetti C, Bignami E, Scandroglio AM, Dedola E, et al.
Pharmacological preconditioning in patients undergoing mitral surgery with or without
concomitant ischaemic disease. J Cardiothorac Vasc Anesth 2007, In press.

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