Year : 2009 | Volume
: 12 | Issue : 1 | Page : 4--9
Halogenated anaesthetics and cardiac protection in cardiac and non-cardiac anaesthesia
Giovanni Landoni, Elena Bignami, Fochi Oliviero, Alberto Zangrillo
Department of Cardiothoracic Anesthesia and Intensive Care, UniversitÓ Vita-Salute San Raffaele, Milano, Italia e Istituto Scientifico San Raffaele, Milano, Italy
Department of Cardiothoracic Anesthesia and Intensive Care, Istituto Scientifico San Raffaele, Milano, Italia. Via Olgettina 60 Milano, 20132
Volatile anaesthetic agents have direct protective properties against ischemic myocardial damage. The implementation of these properties during clinical anaesthesia can provide an additional tool in the treatment or prevention, or both, of ischemic cardiac dysfunction in the perioperative period. A recent meta-analysis showed that desflurane and sevoflurane reduce postoperative mortality and incidence of myocardial infarction following cardiac surgery, with significant advantages in terms of postoperative cardiac troponin release, need for inotrope support, time on mechanical ventilation, intensive care unit and overall hospital stay. Multicentre, randomised clinical trials had previously demonstrated that the use of desflurane can reduce the postoperative release of cardiac troponin I, the need for inotropic support, and the number of patients requiring prolonged hospitalisation following coronary artery bypass graft surgery either with and without cardiopulmonary bypass. The American College of Cardiology/American Heart Association Guidelines recommend volatile anaesthetic agents during non-cardiac surgery for the maintenance of general anaesthesia in patients at risk for myocardial infarction. Nonetheless, e vidence in non-coronary surgical settings is contradictory and will be reviewed in this paper together with the mechanisms of cardiac protection by volatile agents.
|How to cite this article:|
Landoni G, Bignami E, Oliviero F, Zangrillo A. Halogenated anaesthetics and cardiac protection in cardiac and non-cardiac anaesthesia.Ann Card Anaesth 2009;12:4-9
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Landoni G, Bignami E, Oliviero F, Zangrillo A. Halogenated anaesthetics and cardiac protection in cardiac and non-cardiac anaesthesia. Ann Card Anaesth [serial online] 2009 [cited 2020 Jul 2 ];12:4-9
Available from: http://www.annals.in/text.asp?2009/12/1/4/45006
Anaesthetics have cardiac depressant effects that decrease myocardial oxygen demand and may have a beneficial role on myocardial oxygen balance during ischemia. Experimental evidence exist that volatile anaesthetic agents also have direct protective properties against ischemic myocardial damage. Implementation of these properties during clinical anaesthesia can provide an additional tool in the treatment or prevention of ischemic cardiac dysfunction in the perioperative period. 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 anaesthetic or haemodynamic effects of these drugs appear to be involved. We will hereby summarise the clinical findings on the cardioprotective properties of volatile agents in cardiac anaesthesia.
The most recent American College of Cardiology/American Heart Association Guidelines recommend the use of volatile anaesthetic agents during non-cardiac surgery for the maintenance of general anaesthesia in patients at risk for MI,  despite the lack of evidence in this setting.  We will also review the first clinical attempts to perform cardiac protection with volatile anaesthetics in patients undergoing non-cardiac anaesthesia.
Mechanisms of Action
Halogenated agents mimic ischaemic preconditioning (IPC), a powerful cardioprotective phenomenon first described in 1986,  which represents an adaptive response to brief sublethal episodes of ischaemia leading to a pronounced protection against subsequent lethal ischaemia. Clinical application of ischaemic preconditioning (IPC) in patients is not easily feasible because IPC has an intrinsic risk of worsening the condition of an already jeopardised myocardium.
The potential cardiac protective effects of volatile anaesthetics were actually discovered before the concept of anaesthetic preconditioning had been investigated. In 1988, Warltier et al.  demonstrated that pretreatment with halothane or isoflurane improved left ventricular systolic function after a 15-min left anterior descending coronary artery (LAD) occlusion. Nine years later, Cason et al.  showed that a short exposure to isoflurane prior to ischaemia triggers a signal that protects the myocardium, thus introducing the concept of anaesthetic preconditioning (APC). Since then a wealth of data regarding cardiac protection by anaesthetics has been produced and well-designed animal studies have repeatedly demonstrated that exposure of the myocardium to a volatile anaesthetic 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.
APC 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 ) APC, lasting around one or 2 h, and a late preconditioning, reappearing after 24 h and lasting up to 72 h. 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. Adenosine triphosphate-dependent potassium channels on mitochondrial membranes, reactive oxygen species, the apoptotic cascade, nitric oxide, calcium intracellular overload, all appear to play a role in preconditioning. Volatile anaesthetics also reduce neutrophil and platelet adhesion to the vascular wall after ischaemia.
Volatile anaesthetics can also induce protection when administered after ischaemia, during the reperfusion period. The authors who first described ischaemic post-conditioning had noticed that the application of brief periods of ischaemia during reperfusion resulted in a powerful cardioprotection.  Several possible pathways have been identified, including attenuation of nuclear factor kB (NFkB) activation and reduced expression of tumour necrosis factor α(TNFα), interleukin 1 (IL1), intracellular adhesion molecules, eNOS, reduction of the hypercontraction that follows reperfusion, or to anti-apoptotic kinases activation (Akt, ERK 1-2).
Only recently research has turned to clinical implementation of preconditioning, and experimental protocols have been turned into clinical ones:  APC has indeed been demonstrated in randomised clinical trials conducted in patients undergoing cardiac surgery - mostly coronary artery bypass graft. Myocardial ischaemia 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 anaesthetic agent was published in 1999  and showed that administration of isoflurane prior to aortic cross-clamping resulted in smaller postoperative release of creatine kinase MB (CK-MB) and cTn even if this reduction in cardiac biomarkers did not reach a statistic significance due to the small sample of studied patients. Julier et al., in 2003,  were the first to demonstrate that translocation of PKC - one of the mechanisms implicated as a pivotal step in anaesthetic 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. ,,,,,
A key question is whether the cardioprotective effects of volatile anaesthetics 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 anaesthetic agent does not result in a different outcome.  The first study to suggest that the use of halogenated anaesthetics might have relevant clinical advantages was conducted in 2002.  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. ,
De Hert et al. also showed that the cardioprotective effects (lower postoperative cTnI release and preservation of postoperative cardiac function) of an anaesthetic regimen with sevoflurane are most apparent when the volatile anaesthetic is administered throughout the entire surgical procedure as compared to administration only before or after cardiopulmonary bypass (CPB).  Murphy et al. showed how the choice of morphine instead of fentanyl may allow an APC protocol to yield a better cardiac function following CABG.  These data support the idea that the cardioprotective effects of anaesthetic 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 function. 
A Meta-Regression of 34310 CABG Procedures
Seccareccia et al  conducted a longitudinal study of 34,310 CABG interventions, performed between 2002 and 2004 in 64 Italian cardiosurgical centres. They estimated a risk-adjusted mortality ratio (RAMR) for each centre. A national survey among the same 64 cardiosurgical centres was performed in order to investigate whether the use of volatile anaesthetics in that time period showed a correlation with the RAMR.  The results show that 30 days risk-adjusted mortality is significantly reduced when volatile agents are used during cardiac surgery. Isoflurane, the cheapest and older drug among those studied, was the one with the most consistent results. In particular, RAMR was lowest in those centres which used volatile anaesthetics for the majority of their cardiac surgical interventions and highest in those which only used intravenous anaesthetics.
A Meta-Analysis of 22 Randomised Controlled Studies in Cardiac Surgery
A recent meta-analysis showed that desflurane and sevoflurane reduce postoperative mortality and incidence of myocardial infarction (MI) following cardiac surgery with significant advantages in terms of postoperative cardiac troponin (cTn) release, need for inotropic support, time on mechanical ventilation, intensive care unit (ICU) and overall hospital stay.  This is the first study to show that the choice of an anaesthetic plan can result in lower mortality and morbidity in patients undergoing surgery. An extensive search in BioMedCentral and PubMed, the scanning of references of retrieved articles and pertinent reviews and contacts with international experts led to the identification of 22 randomised clinical trials that compared a TIVA versus an anaesthesia 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 review was the rate of in-hospital MI as per author definition, while the co-primary end-point was the rate of hospital mortality. The 22 included trials randomised 1922 patients (904 to TIVA and 1018 receiving desflurane or sevoflurane in their anaesthesia plan). 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 mitral surgery. Most authors administered volatile anaesthetics throughout all the procedures, while 6 of them administered them for a short time (5 to 30 minutes) and only before or during the expected cardiac damage. Volatile anaesthetics 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 were multi-centric, while the rest had a single-centre design. Overall analysis showed that, in comparison to TIVA, volatile anaesthetics were associated with significant reductions in the rates of all major endpoints. Specifically, volatile anaesthetics reduced the risk of myocardial infarction (MI) (24/979 [2.4%] in the volatile anaesthetics group vs 45/874 [5.1%] in the control arm, odds ratio (OR) = 0.51 [0.32-0.84], p for effect = 0.008, p for heterogeneity = 0.77, I 2 = 0%) 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, I 2 = 0%). Beside increasing in-hospital survival, use of volatile anaesthetics was also associated with a significant reduction in cTnI peak release (WMD -2.35 ng/dl [-3.09,-1.60], p for effect p for heterogeneity 2 = 94.1% with 1463 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 p for heterogeneity = 0.008, I 2 = 53.1% with 1241 included patients). Furthermore, the use of desflurane and sevoflurane was associated with shorter ICU stay (WMD = -7.10 h [-11.47; -2.73], p for effect p for heterogeneity 2 = 76.6% with 1433 included patients), time to hospital discharge (WMD = -2.26 days [-3.83; -0.68], p for effect = 0.005, p for heterogeneity 2 = 93.7% with 1593 included patients) and time on mechanical ventilation (WMD =-0.49 h [-0.97; -0.02], p for effect =0.04, p for heterogeneity 0.03, I 2 = 44.1% with 1846 included patients). Finally, only two studies reported one-year follow-up data concerning major cardiac events (defined as cardiac death, non-fatal MI, unstable angina, intercurrent coronary angioplasty, coronary artery bypass grafting, arrhythmias requiring hospitalisation and new episodes of congestive heart failure): 4/48 [8.3%] in the volatile anaesthetics 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, I 2 = 0%).
Multicentre Evidence in Cardiac Surgery
Multicentre, randomised clinical trials (RCT) had previously demonstrated that the use of desflurane can reduce the postoperative release of cardiac troponin I (cTnI), the need for inotropic support, and the number of patients requiring prolonged hospitalisation following coronary artery bypass graft (CABG) surgery either with  and without  cardiopulmonary bypass.
Nonetheless, whether volatile anaesthetics improve the outcome of cardiac surgical patients is still matter of debate. In a retrospective, non-randomised study including more than 10,000 cardiac surgical patients, Jakobsen et al .  compared sevoflurane and a total intravenous anaesthesia (TIVA). The authors found no difference in postoperative mortality and myocardial infarction rate; patients without preoperative unstable angina or recent myocardial infarction, however, showed a lower postoperative mortality after sevoflurane anaesthesia. Although this study carries some others limitations in its design - such as the fact that cardioprotective strategies and surgical and anaesthetic teams varied across the three participant centres - it yields some interesting evidence over a very large number of patients.
Non-Coronary Cardiac Surgery
Evidence in non-coronary surgical settings is even more contradictory. Landoni et al . found no advantage in using a preconditioning protocol with volatile anaesthetics in patients undergoing coronary mitral surgery.  Interestingly, patients undergoing mitral surgery with concomitant coronary artery disease showed a marked decrease in postoperative cTnI release when preconditioned with desflurane.  In another study on a small group of patients undergoing aortic valvular replacement,  Cromheecke et al . found that sevoflurane-based anaesthesia reduced postoperative cTnI dismissal. They also observed that patients anaesthetised with sevoflurane had an advantage in terms of minor clinical outcomes, such as the incidence of atrial fibrillation and ICU stay.
Landoni and co-worker investigated the cardioprotective properties of volatile anaesthetics in the setting of stenting procedures.  The authors randomly assigned 16 patients to breathe sevoflurane (expired end-tidal concentration 1%) and 14 patients to breathe a placebo oxygen/air mix before stenting procedures. The patients were requested to breathe spontaneously oxygen 50% and air (fresh gas flow 12 L) delivered through a tight fitting, occlusive mask (held by the anaesthesiologist and connected to the breathing circuit and gas-scavenging system of a Draeger anaesthesia machine). Patients in the volatile anaesthetics group breathed sevoflurane 0.5 end-tidal minimum alveolar concentration (MAC) (1%) for 20 min. Patients in the placebo group simply breathed oxygen and air. At the end of the 20 min, the patients entered into the washout period, spontaneously breathing air. Ten minutes after the washout period, patients were transferred to the cardiac catheterisation lab for percutaneous coronary intervention with stent implantation. Sixteen patients had detectable cTnI after stenting procedures with no differences between groups: 10 (62%) in the sevoflurane group versus 6 (43%) in the placebo group ( p = 0.3). No differences in the amount of post-procedural median (interquartile range) cTnI release was noted between the sevoflurane group, 0.15 (0-4.73) ng/mL, and the placebo group, 0.14 (0-0.87) ng/mL ( p = 0.4). The authors concluded that patients receiving low-dose sevoflurane as a pharmacologic preconditioning agent before interventional cardiology procedures have no reduction in myocardial damage compared with patients receiving placebo.
Clinical Evidence in Non-Cardiac Surgery
Recent American College of Cardiology/American Heart Association Guidelines recommended volatile anaesthetic agents during non-cardiac surgery for the maintenance of general anaesthesia in patients at risk for MI (class IIa, level of Evidence B), but whether halogenated anaesthetics also have cardioprotective properties in non-cardiac surgery settings is controversial. 
A recent meta-analysis  included 79 studies, involving 6219 patients (2768 received TIVA and 3451 received desflurane or sevoflurane in their anaesthesia plan) undergoing non-cardiac surgery. Inclusion criteria were random allocation to treatment, comparison of a TIVA regimen vs an anaesthesia plan including desflurane or sevoflurane, performed on adult, non-cardiosurgical patients. All authors administered volatile or intravenous anaesthetics throughout the procedure. Volatile anaesthetic dosage varied across studies, ranging 0.33-2 MAC in the 609 patients receiving desflurane and 0.25-2 MAC in the 2842 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 randomised study among those which compared halogenated to intravenous anaesthetics has addressed major outcomes such as MI or mortality.
A recent report has found, for the first time, a reduction in troponin release after thoracic surgery.  The authors of this randomised controlled study, including 27 patients (13 receiving sevoflurane 14 receiving propofol as their main anaesthetic agent), measured peak postoperative troponin I release as a marker of myocardial necrosis. One (7.7%) patient in the sevoflurane group had a detectable postoperative cardiac troponin I versus 6 (42.9%) patients in the propofol group ( p = 0.048). Mortality did not differ between the two groups (1/13 vs 0/14, p = ns).
Halogenated agents have non-anaesthetic 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.
This review supports the evidence that the choice of an anaesthetic regimen was shown to have an impact on patients' outcome following cardiac surgery.  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 bypass.  These results are in accordance with those of the above described meta-regression. 
A recent meta-analysis  has shown for the first time that the use of desflurane and sevoflurane in an anaesthetic 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 already recommend the use volatile anaesthetic agents during non-cardiac surgery for the maintenance of general anaesthesia in patients at risk for MI. 
Large, multicentre, randomised clinical trials including patients undergoing cardiac and possibly high-risk non-cardiac surgery are needed to achieve a definitive demonstration of anaesthetic-induced cardioprotection: this represents a difficult task because of the low mortality rate in modern surgery and because of the number of interfering factors.
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