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REVIEW ARTICLE
Endorsed by
105
Volatile anaesthetic myocardial
protection: a review
of the current literature
E. Lin, J.A. Symons
Department of Anaesthesia and Perioperative Medicine, Alfred Hospital, Monash University; Melbourne, Australia
HSR Proceedings in Intensive Care and Cardiovascular Anesthesia 2010; 2: 105-109
ABSTRACT
Ischaemic preconditioning is a powerful innate adaptive phenomenon whereby brief periods of sublethal isch-
aemia result in marked tolerance to subsequent lethal ischaemia. Halogenated anaesthetics have been shown
to mimic ischaemic preconditioning, modifying and attenuating ischaemia reperfusion injury.
This review aims to present the current animal and human data, discuss the possible mechanisms of action
and review the clinical evidence for volatile anaesthetic-induced myocardial protection.
There is class Ia evidence for the myocardial protective properties of sevoflurane and desflurane in low risk
patients undergoing coronary artery bypass grafting surgery.
These volatile anaesthetics have been shown to improve clinical outcomes and health economics following
cardiac surgery, reducing intensive care and hospital stay. The evidence for the benefit of volatile anaesthetics
in non-cardiac surgery is less robust and further large randomized controlled trials are required to elucidate
this question.
Keywords: volatile anaesthetics, myocardial protection, ischaemic preconditioning, mechanisms, cardiac anaes-
thesia, outcomes.
InTRoduCTIon Mechanism of myocardial protection
Ischaemic preconditioning is a powerful in-
There is strong evidence for volatile anaes-
nate adaptive phenomenon discovered by
thetic induced myocardial protection in ex-
Murry and colleagues (1), whereby brief
perimental studies.
periods of sublethal ischaemia results in
Despite this weight of evidence in animal
marked tolerance to subsequent lethal isch-
studies, the translational into human trials
aemia. Halogenated anaesthetics have been
has borne less consistent results.
shown to mimic ischaemic precondition-
This review aims to present the current an-
ing, modifying and attenuating ischaemia
imal and human data, discuss the possible
reperfusion injury (2).
mechanisms of action and review the clini-
Two periods of ischaemic preconditioning
cal evidence.
have been described; early or classical pre-
conditioning that occurs immediately, and
induces potent protection that lasts one to
Corresponding author: two hours.
Joel A Symons, MD
Late preconditioning or the second win-
Department of Anaesthesia and Perioperative Medicine,
Alfred Hospital, Monash University dow of preconditioning occurs 24 hours
Victoria, 3800 - Melbourne, Australia
after the initial stimulus, induces a less pro-
e.mail: [email protected]
HSR Proceedings in Intensive Care and Cardiovascular Anesthesia 2010, Vol. 2
E. Lin, J.A. Symons
106 nounced cardio-protection, but lasts for up ly separate these two protective effects of
to 72 hours (3). volatile anaesthetics on the myocardium.
Early and late preconditioning probably This is best demonstrated by the fact that
involves different signalling pathways that studies have also suggested the maximum
have yet to be fully elucidated. Early pre- protection is yielded by the administration
conditioning is thought to involve opening of volatile anaesthetics throughout the op-
mitochondrial ATP dependent potassium erative procedure (18).
channels (4-9), increasing mitochondrial
reactive oxygen species (4, 10, 11), decreas- Clinical evidence in cardiac surgery
ing cytosolic and mitochondrial calcium Since 1985, when Freedman and colleagues
loading (12), protection of endothelial (19) reported that enflurane could im-
coronary cells by mediating nitric oxide prove post-ischemic myocardial recovery,
release (13) and by suppressing neutrophil there has been extensive research into the
activation and the neutrophil-endothelium potential benefits of anaesthetic myocar-
interactions that cause myocardial dysfunc- dial protection in both animal and human
tion (14, 15). models. The majority have been performed
Pathways of late preconditioning involve on patients undergoing CABG (coronary
attenuation of nuclear factor kB (NFkB), artery bypass grafting). Unfortunately, to
activation and reduced expression of tu- date, these studies have been observational
mour necrosis factor k (TNFk), interleu- in nature or if randomized have been too
kin 1 (IL1), intracellular adhesion mol- small and underpowered to identify effects
ecules, eNOS, a reduction of the hyper- on significant outcomes such as myocardial
contraction that follows reperfusion and infarction and mortality. Studies have gen-
activation of anti-apoptotic kinases (Akt, erally used surrogate markers for myocardi-
ERK 1-2) (2). al protection such as the cardiac troponins
Volatile anaesthetics have been shown in a as a measure of myocardial injury.
number of animal ex vivo and in vivo ex- To date there have been 3 meta-analyses
periments to be able to precondition the performed including only randomized con-
myocardium in a similar way to classical trolled trials (RCTs) to try and answer the
ischaemic preconditioning. Similarly, vol- question does volatile anaesthesia improve
atile anaesthetics have the ability to post- outcomes in coronary surgery?
condition the myocardium whereby ex- Yu and Beattie performed the first meta-
posure to volatiles during the reperfusion analysis in 2006 (20). The authors identi-
period also protects the myocardium (16). fied 32 randomized studies involving 2841
There is now increasing evidence that vola- patients. Volatile anaesthetics included hal-
tile anaesthetics can induce late precondi- othane, enflurane, isoflurane, sevoflurane
tioning, raising the potential of myocardial and desflurane and were administered in
protection that persists after the exposure any combination of the pre-bypass, during
in the operating theatre (16, 17). bypass and post-bypass periods. When com-
In addition to the ability to precondition pared with intravenous anaesthetics, those
the myocardium, all volatile anaesthet- who were exposed to volatile anaesthetics
ics induce a dose dependent decrease in had an observed reduction in mortality that
myocardial contractility, decrease myocar- did not reach statistical significance (OR,
dial oxygen demand and therefore improve 0.65; 95% CI 0.36-1.18). Furthermore, re-
myocardial oxygen balance during isch- moving studies that used halothane or en-
aemia. It is often difficult to experimental- flurane in their study protocols also failed
HSR Proceedings in Intensive Care and Cardiovascular Anesthesia 2010, Vol. 2
Volatile anaesthetic myocardial protection
to show a statistically significant reduction ics throughout the entire procedure. Only 107
in mortality. Similarly, no statistical differ- a few of the RCTs were of high quality and
ence was seen in the incidence of AMI be- all the studies included numbers that were
tween groups. However, post hoc analysis too small to allow for assessment of impor-
of patients that received sevoflurane or des- tant clinical outcome variables such as AMI
flurane showed that these patients experi- and death.
enced significantly less Troponin I leakage Data pooling and analysis showed that
than patients receiving intravenous anaes- when compared with intravenous anaes-
thesia. thesia, sevoflurane and desflurane were
Symons and Myles performed a similar associated with significant reductions in
meta-analysis in 2006 (21). They identified the rates of all major clinical outcome vari-
27 randomized studies including 2979 pa- ables. Volatile anaesthesia significantly re-
tients comparing volatile with non-volatile duced the degree of troponin I leakage (OR
anaesthesia for CABG. Volatile anaesthetics 0.47; 0.29, 0.76). Importantly, the risk of
again included halothane, enflurane, isoflu- all-cause mortality and AMI was also sig-
rane, sevoflurane and desflurane and were nificantly reduced by volatile anaesthesia
administered during pre-bypass, bypass and (OR 0.31; 0.12,0.80 and OR 0.51; 0.32,0.84
post-bypass periods. There was no signifi- respectively). Furthermore, the use of sevo-
cant difference between volatile and non- flurane and desflurane was associated with
volatile anaesthetic groups with respect to a significant reduction in the duration of
death, myocardial infarction, myocardial mechanical ventilation, length of ICU stay
ischaemia or ICU length of stay. However, and time to hospital discharge.
patients randomized to receive volatile an- Though this represents strong class Ia evi-
aesthetics had significantly higher cardiac dence for myocardial protection with mod-
indices, lower troponin I concentrations, ern volatile anaesthetic agents in patients
reduced requirement for inotropic support, undergoing CABG, results from a large ob-
shorter duration of mechanical ventilation servational study published in 2007 are not
and shorter length of hospital stays than quite so conclusive. Data from a retrospec-
those randomized to receive intravenous tive Danish database of 10,535 patients un-
anaesthetics. The results indicated that dergoing cardiac surgery with sevoflurane
volatile anaesthetics may indeed be able to or propofol anaesthesia showed no differ-
change outcomes in cardiac surgery. ence in overall post-operative mortality or
More recent animal evidence suggests that myocardial infarction (28). The group sur-
sevoflurane and desflurane display more mise that both propofol and sevoflurane
prominent cardioprotection than the older have different cardioprotective properties.
halogenated anaesthetics (22-26). This lead Sub-group analysis revealed that in patients
to the most recent meta-analysis performed undergoing non-coronary cardiac surgery,
by Landoni and colleagues in 2007 (27). sevoflurane was superior to propofol whilst
Their group identified 22 randomised stud- propofol was superior to sevoflurane in
ies involving 1922 patients where compari- patients with severe ischaemia, cardiovas-
sons of the modern volatile anaesthetics cular instability or those requiring urgent
sevoflurane and desflurane were made with surgery. This finding may reflect the anti-
intravenous anaesthesia in CABG surgery. oxidant properties of propofol and the isch-
Most studies were performed on patients aemic preconditioning effect of unstable
undergoing on-pump CABG and most au- angina negating the myocardial protection
thors administered the volatile anaesthet- offered by volatile anaesthesia.
HSR Proceedings in Intensive Care and Cardiovascular Anesthesia 2010, Vol. 2
E. Lin, J.A. Symons
108 Clinical evidence in non-cardiac surgery 2. Landoni G, Bignami E, Oliviero F, Zangrillo A.
Landoni and colleagues performed a meta- Halogenated anaesthetics and cardiac protection
in cardiac and non-cardiac anaesthesia. Ann Card
analysis of RCTs comparing sevoflurane or
Anaesth 2009; 12: 4-9.
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3. Yellon DM, Downey JM. Preconditioning the myo-
anaesthesia in adult patients undergoing cardium: from cellular physiology to clinical cardi-
non-cardiac surgery in 2007 (29). Seventy- ology. Physiol Rev 2003; 83: 1113-1151.
4. de Ruijter W, Musters RJ, Boer C, et al. The car-
nine studies and over 6000 patients were
dioprotective effect of sevoflurane depends on pro-
included in the analysis but firm conclu-
tein kinase C activation, opening of mitochondrial
sions could not be made due to the low K+ATP channels, and the production of reactive
incidence of cardiovascular events in both oxygen species. Anesth Analg 2003; 97: 1370-
groups. 1376.
5. Hanouz J-L, Yvon A, Massetti M, et al. Mechanisms
Nevertheless, the most recent American
of desflurane-induced preconditioning in isolated
College of Cardiology/American Heart As-
human right atria in vitro. Anesthesiology 2002;
sociation Guidelines recommend the use 97: 33-41.
of volatile anaesthetic agents during non- 6. Hara T, Tomiyasu S, Sungsam C, et al. Sevoflurane
cardiac surgery in patients at risk for AMI protects stunned myocardium through activation of
mitochondrial ATP-sensitive potassium channels.
(Class IIa, level B) (30).
Anesth Analg 2001; 92: 1139-1145.
7. Nakae Y, Kohro S, Hogan QH, Bosnjak ZJ. Intra-
cellular mechanism of mitochondrial adenosine tri-
ConCLuSIonS phosphate-sensitive potassium channel activation
with isoflurane. Anesth Analg 2003; 97: 1025-1032.
8. Zaugg M, Lucchinetti E, Spahn DR, et al. Volatile
There is class Ia evidence for the myocardi- anesthetics mimic cardiac preconditioning by prim-
al protective properties of sevoflurane and ing the activation of mitochondrial KATP channels
desflurane in low risk patients undergoing via multiple signalling pathways. Anesthesiology
2002; 97: 4-14.
coronary artery bypass grafting surgery.
9. Zaugg M, Lucchinetti E, Spahn DR, et al. Differen-
The modern volatile anaesthetics have
tial effects of anesthetics on mitochondrial KATP
been shown to improve clinical outcomes channel activity and cardiomyocyte protection. An-
and health economics following cardiac esthesiology 2002; 97: 15-23.
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robust and further large randomized con- of preconditioning by isoflurane in rabbits: a direct
role for reactive oxygen species. Anesthesiology
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2002; 97: 1485-1490.
question. Furthermore, volatile anaesthetic
12. Varadarajan SG, An J, Novalija E, Stowe DF. Sevo-
protection of organs other than the heart flurane before or after ischaemia improves contrac-
warrants further investigation. tile and metabolic function while reducing myoplas-
mic Ca2+ loading in intact hearts. Anesthesiology
No conflict of interest acknowledged by the authors. 2002; 96: 125-133.
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