Journal of Cardiothoracic and Vascular Anesthesia
Volume 20, Issue 4 , Pages 473-476, August 2006

Anesthetic Preconditioning: How Important Is It in Today’s Cardiac Anesthesia?

Department of Anesthesiology, University Hospital Antwerp, Edegem, Belgium

Article Outline

 

OVER THE PAST 2 decades, increasing experimental evidence has indicated that volatile anesthetic agents have cardioprotective properties, which cannot only be explained by their beneficial effects on the myocardial oxygen balance. Instead, these agents also appear to exhibit direct cardioprotective properties. This protective action was observed when administering the agents both before myocardial ischemia (preconditioning) but also after ischemia during early reperfusion (postconditioning).1, 2, 3

Anesthetic preconditioning (APC) refers to the phenomenon whereby exposure of the heart to a volatile anesthetic before myocardial ischemia results in protection against the deleterious effects of myocardial ischemia and reperfusion. Compared with control conditions, this protection manifests as an improvement at the level of different variables such as infarct size and contractile function, but also coronary flow and free radical release at reperfusion. This type of protection strongly resembles ischemic preconditioning (IPC), which is a powerful endogenous protective mechanism that is present at different organ levels and occurs in various species. IPC refers to the phenomenon whereby a brief period of ischemia is able to protect the myocardium (ie, precondition) against the reversible and irreversible consequences of a subsequent longer period of ischemia, such as stunning, infarction, and the occurrence of arrhythmias. The mechanisms underlying IPC involve a complex system of intracellular signalling pathways, many of which are shared by APC. In addition, recent experimental data have indicated that APC is able to confer additional cardioprotection after IPC.4

The straightforward beneficial effects of experimental APC protocols on postischemic reversible and irreversible myocardial damage have prompted clinicians to explore whether application of such protocols in perioperative patient care could help to improve patients’ outcome. This was especially challenging because previous clinical investigations found no evidence that the choice of one anesthetic agent was preferable to another for patients with coronary artery disease.5, 6

This issue has been addressed only very recently. Until then, the potential application of preconditioning protocols was mainly confined to an evaluation of IPC protocols or associated pharmacologic manipulation of the pathways involved in IPC. Despite initial enthusiasm, the implementation of such protocols in perioperative patient care has not met the expectations. Indeed, a justified concern remains with regard to IPC protocols in coronary patients, in whom provoking a short ischemic burden as preconditioning stimulus may further jeopardize the already diseased myocardium. The pharmacologic modulation of the protective pathways involved in IPC also did not reach routine clinical application, mainly because of the side effects associated with the compounds studied.

These concerns are not present with the use of APC protocols, and as such, volatile anesthetics; but also other agents with APC properties such as opiates, might very well constitute the first classes of drugs that allow for implementation of pharmacologic preconditioning protocols in patient care.

In contrast to the huge number of experimental studies published, data on clinical APC protocols are limited. This can partly be explained by the fact that a prerequisite to study effects of preconditioning protocols is the occurrence of a standardized ischemic insult. Whereas this is readily obtained in an experimental setting, this is not true for clinical research protocols. The only perioperative setting in which such a situation may be present is cardiac surgery, which is probably the reason why all clinical APC protocols until now have been performed in cardiac surgery patients. Table 1 summarizes methodologic aspects and main results of the clinical APC studies that have been published most recently.7, 8, 9, 10, 11, 12, 13, 14 Taken together, the results of these studies indicate that APC is probably also present in humans. However, its implication for protection against the consequences of reversible and irreversible myocardial damage after ischemia seems, in contrast to the results obtained in experimental studies, questionable.

Table 1. Overview of the Clinical Anesthetic Preconditioning Protocols
Methodologic Aspects EffectReference
Isoflurane 2.5 MAC on CPB with heart totally decompressed before aortic cross-clamping
Study group: n = 10

5 min PC followed by 10 min washout

Control group: n = 10
Lower Tnl and CK-MB release in study group (not significant)

Higher 5′ nucleotidase activity (∼ PKC activation)

No functional data

7
Enflurane before CPB
Study group: n = 8

5 min PC before start CPB, no washout

Control group: n = 8
Preserved cardiac function in study group

Tnl and CK-MB not different between groups

8
Isoflurane before CPB
Study group: n = 20

15 min PC followed by 10 min washout

Control group: n = 20
Myocardial function not different between groups

Tnl and CK-MB not different between groups

9
Isoflurane before CPB
Study group: n = 28

No washout

Control group: n = 21

Better cardiac index in study group10
Sevoflurane 2.5 MAC on CPB before aortic cross-clamping
Study group: n = 10

10 min PC without washout

Control group: n = 10
Increased TK activity in study group

Increased PKC and p38 MAPK in both groups

No functional data

11
Sevoflurane 2 MAC on CPB with heart totally decompressed before aortic cross-clamping
Study group: n = 37

10 min PC without washout

Control group: n = 35
Decreased BNP release in study group

TnT and CK-MB not different between groups

Activation of PKC δ and ϵ isoforms

No functional data

12
Isoflurane before CPB; not randomized assignment; no administration protocol
Study group: n = 138

Control group: n = 221
No difference in Tnl release

No difference in in-hospital outcome

13
Isoflurane before CPB; diabetic patients on glibenclamide
Control group: n = 10

Study group 1: n = 10

15 min PC followed by 10 min washout

Study group 2: n = 10

Conventional anesthesia + shift to insulin

Study group 3: n = 10

PC protocol + shift to insulin
Lower Tnl and CK-MB in study groups

Tnl and CK-MB not different between groups

14

Abbreviations: CPB, cardiopulmonary bypass; MAC, minimal alveolar concentration; TnI, troponin I; CK, creatine kinase; PKC, protein kinase C; TK, tyrosine kinase; MAPK, mitogen-activated protein kinase; BNP, brain natriuretic peptide.

Does this imply that APC should be abandoned as a potential therapeutic tool in the perioperative treatment of patients with coronary artery disease? When looking in detail at the methodologies used in the different clinical APC studies, a striking inhomogeneity in experimental setups becomes apparent. Indeed, among others, different time periods of APC were used; some protocols included a washout phase (which is by definition a prerequisite for the preconditioning phenomenon), whereas others did not, and finally duration of ischemia and anesthetic preconditioning were different in the various studies. It is therefore not really surprising that conflicting data on clinical benefits of APC protocols are reported.

The importance of the different modalities of administration of APC is further underscored by the data obtained in studies in which the volatile anesthetic agents were given throughout the entire operation (Table 2).15, 16, 17, 18 In these studies, a more straightforward clinically relevant protective effect, both on markers of postoperative myocardial function and on markers of myocardial damage, was observed. This was confirmed by comparing the postoperative release of biochemical markers of myocardial damage and immediate postoperative myocardial function in patients having a volatile anesthetic agent throughout the entire procedure compared with patients to whom the volatile anesthetic was administered only during a limited period before ischemia or after completion of the coronary anastomoses.19 The results of this study indicated that the cardioprotective effects of a volatile anesthetic regimen were clinically most apparent when the agent was administered throughout the entire surgical procedure. This was evident from a lower postoperative troponin I release and a preservation of postoperative cardiac function when compared with a total intravenous anesthetic regimen. When administered only as an APC protocol or only during reperfusion (postconditioning), postoperative recovery of stroke volume occurred earlier and postoperative release of troponin I was slightly lower than with the intravenous anesthetic regimen, although this difference did not reach statistical significance.

Table 2. Clinical Protocols on Cardioprotective Effects of Volatile Anesthetics When Administered Throughout the Entire Procedure
Methodologic Aspects EffectReference
Sevoflurane v propofol throughout

Coronary artery surgery with CPB

Patients with preserved myocardial function
Study group: n = 10 (sevoflurance)

Control group: n = 10 (propofol)
Lower Tnl release in study group

Better preserved myocardial function in study group

15

Sevoflurane v propofol throughout

Coronary artery surgery with CPB

Patients with impaired myocardial function
Study group 1: n = 15 (sevoflurane)

Study group 2: n = 15 (desflurane)

Control group: n = 15 (propofol)
Lower Tnl release in study groups

Better preserved myocardial function in study groups

16

Sevoflurane v propofol throughout

OPCAB surgery
Study group: n = 10 (sevoflurane)

Control group: n = 10 (propofol)
Lower Tnl release in study groups

Better preserved myocardial function in study group

17

Sevoflurane v propofol throughout

OPCAB surgery
Study group: n = 24 (sevoflurane)

Control group: n = 26 (propofol)
No difference in Tnl release between groups

Better preserved myocardial function in study group

18

Abbreviations: CPB, cardiopulmonary bypass; OPCAB, off-pump coronary artery bypass; TnI, troponin I.

These data indicate that the choice for a specific anesthetic regimen may help in the protection of the myocardium from the consequences of reversible and irreversible ischemic injury in the perioperative period. They, however, also show that the extent and magnitude of these protective effects may strongly depend on the modalities of their administration. The present issue of the Journal of Cardiothoracic and Vascular Anesthesia contains 3 articles that nicely show how the cardioprotective effects of anesthetic agents may depend on a complex interaction of subtle elements such as the choice of a specific anesthetic agent, the administration protocols, the presence and duration of pre- and perioperative myocardial ischemia, the patient population studied, and the variables used to assess myocardial function. For instance, the study of Murphy et al20 suggests that an APC protocol with morphine but not with fentanyl protects the myocardium after cardioplegic arrest and cardiopulmonary bypass. This conclusion is based on the observation that an echocardiographic variable of global cardiac function, the myocardial performance index, showed a better profile in the patients receiving morphine than in those receiving fentanyl before myocardial ischemia. Interestingly, other variables of hemodynamic function or measurements of myocardial damage (TnI) or dysfunction (brain natriuretic peptide) failed to show a difference between the treatments. Another study by Law-Koune et al21 compared sevoflurane-remifentanil with propofol-remifentanil anesthesia in 18 patients undergoing off-pump coronary artery surgery and failed to show any cardioprotective effect of the volatile anesthetic regimen. This finding contradicts earlier data obtained by Conzen et al17 and Bein et al18 in a similar study population. Several methodologic issues might contribute to these apparently conflicting results, among which a number have been addressed by the authors. A major contributing factor, apart from the small study population, might be related to the duration and extent of preoperative and perioperative myocardial ischemia. Finally, the study of Landoni et al22 observed a beneficial effect on postoperative troponin I release with a volatile anesthetic regimen in patients undergoing off-pump coronary artery surgery, thereby adding new evidence for a potential perioperative cardioprotective effect of a volatile anesthetic regimen in patients with coronary artery disease.

Although most studies indicate that the use of a volatile anesthetic regimen is capable of preserving myocardial function and/or decreasing the extent of postoperative myocardial injury, the real impact of this protective action on patients’ outcome, such as perioperative morbidity and mortality, remains to be established. A retrospective analysis of a Danish database on cardiac operations in 5,945 patients showed a lower mortality after valve surgery and a (statistically not significant) lower mortality rate after coronary artery surgery in patients anesthetized with a volatile agent.23 A recent study reported that the administration of an APC protocol was associated with an improved 1-year cardiovascular outcome after coronary artery surgery.24 Interestingly, the patients who developed a new adverse cardiac event (coronary reocclusion or a new episode of congestive heart failure) had a more pronounced elevation of early postoperative biomarkers of myocardial injury than those without late cardiac events. It can therefore not be excluded that in this study the observed long-term protection is merely the consequence of an early protective effect.

A major problem with outcome studies is that in order to have sufficiently powered observations and the number of patients necessary to detect differences in low-incidence events (such as mortality or perioperative myocardial infarction), the patient population needed is extremely high. Two studies have assessed intensive care unit length of stay with a volatile anesthetic regimen as an outcome variable. It can be considered that a prolonged length of stay represents a “composite endpoint” that reflects the sum of all the trends in adverse outcome of variables such as myocardial infarction and dysfunction, renal failure, stroke, prolonged mechanical ventilation, and others. The use of a volatile anesthetic regimen in patients with coronary artery disease has been associated with a lower intensive care and hospital length of stay.25, 26 A similar observation has been made by Landoni et al22 in their study published in this issue of the journal.

Where do clinicians stand now with respect to their knowledge of the cardioprotective effects of anesthetic agents? Overwhelming experimental evidence indicates that volatile anesthetics and some opiates protect the myocardium against the consequences of reversible and irreversible ischemic damage. Continuing studies will further unravel the underlying mechanisms of these protective actions. The results of these studies will undoubtedly help to improve the administration modalities for the clinical application of such protocols. Indeed, until now, the clinical implications of the cardioprotective properties of volatile anesthetics in patients with coronary artery disease were limited. Only in clinical protocols in which the volatile anesthetic was administered throughout the entire operation, a clear effect on preservation of myocardial function and extent of myocardial damage was observed. Clinical APC protocols mostly did not result in a straightforward and reproducible cardioprotective effect. Therefore, clinical studies will have to elucidate which administration protocols will ultimately be associated with a maximal cardioprotective effect. Secondly, time has come to further establish the clinical significance of anesthetic cardioprotection in humans and its impact on cardiac morbidity and mortality. A first approach to address this issue is by performing a meta-analysis on the available data. However, the ultimate straightforward answer to a possible impact on patients’ outcome will probably necessitate a large-scale multicenter study including thousands of patients. Finally, it is important to remember that patients with coronary artery disease are not confined to cardiac surgery but may also present for all other types of surgery, where they constitute a high-risk population. Further studies will have to evaluate whether the application of anesthetic cardioprotective protocols may also reduce perioperative cardiac morbidity and mortality in these patient populations. The definitive answer to these questions will necessitate much more effort and time. However, with the present knowledge of experimental but also clinical studies, it seems that the use of a volatile anesthetic regimen can constitute an additional therapeutic approach in the care of patients at risk of developing perioperative cardiac complications.

Back to Article Outline

References 

  1. Sommerschild HT , Kirkebøen KA . Preconditioning—Endogenous defense mechanisms of the heart . Acta Anaesth Scand . 2002;46:123–137
  2. Tanaka K , Ludwig LM , Kersten JR , et al.   Mechanisms of cardioprotection by volatile anesthetics . Anesthesiology . 2004;100:707–721
  3. De Hert SG , Turani F , Mathur S , et al.   Cardioprotection with volatile anaesthetics (Mechanisms and clinical implications) . Anesth Analg . 2005;100:1584–1593
  4. Müllenheim J , Ebel D , Bauer M , et al.   Sevoflurane confers additional cardioprotection after ischemic late preconditioning in rabbits . Anethesiology . 2003;99:624–631
  5. Slogoff S , Keats AS . Randomized trial of primary anesthetic agents on outcome of coronary bypass operations . Anesthesiology . 1989;70:179–188
  6. Tuman KJ , McCarthy RJ , Spiess BD , et al.   Does choice of anesthetic agent significantly affect outcome after coronary surgery? . Anesthesiology . 1989;70:189–198
  7. Belhomme D , Peynet J , Louzy M , et al.   Evidence for preconditioning by isoflurane in coronary artery bypass graft surgery . Circulation . 1999;100:II340–II344
  8. Penta de Peppo A , Polisca P , Tomai F , et al.   Recovery of LV contractility in man is enhanced by preischemic administration of enflurane . Ann Thorac Surg . 1999;68:112–118
  9. Tomai F , De Paulis R , Penta de Peppo A , et al.   Beneficial impact of isoflurane during coronary bypass surgery on troponin I release . G Ital Cardiol . 1999;29:1007–1014
  10. Haroun-Bizri S , Khoury SS , Chehab IR , et al.   Does isoflurane optimize myocardial protection during cardiopulmonary bypass? . J Cardiothorac Vasc Anesth . 2001;15:418–421
  11. Pouzet B , Lecharny JB , Dehoux M , et al.   Is there a place for preconditioning during cardiac operations in humans? . Ann Thorac Surg . 2002;73:843–848
  12. Julier K , da Silva R , Garcia C , 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;98:1315–1327
  13. Fellahi JL , Gue X , Philippe E , et al.   Isoflurane may not influence postoperative cardiac troponin I release and clinical outcome in adult cardiac surgery . Eur J Anaesthesiol . 2004;21:688–693
  14. Forlani S , Tomai F , De Paulis R , et al.   Preoperative shift from glibenclamide to insulin is cardioprotective in diabetic patients undergoing coronary artery bypass surgery . J Cardiovasc Surg . 2004;45:117–122
  15. De Hert SG , ten Broecke PW , Mertens E , et al.   Sevoflurane but not propofol preserves myocardial function in coronary surgery patients . Anesthesiology . 2002;97:42–49
  16. De Hert SG , Cromheecke S , ten Broecke PW , et al.   Effects of propofol, desflurane, and sevoflurane on recovery of myocardial function after coronary surgery in elderly high-risk patients . Anesthesiology . 2003;99:314–323
  17. Conzen PF , Fisher S , Detter C , et al.   Sevoflurane provides greater protection of the myocardium than propofol in patients undergoing off-pump coronary artery bypass surgery . Anesthesiology . 2003;99:826–833
  18. Bein B , Renner J , Caliebe D , et al.   Sevoflurane but not propofol preserves myocardial function during minimally invasive direct coronary artery bypass surgery . Anesth Analg . 2005;100:610–616
  19. De Hert SG , Van der Linden PJ , Cromheecke S , et al.   Cardioprotective properties of sevoflurane in patients undergoing coronary surgery with cardiopulmonary bypass are related to the modalities of its administration . Anesthesiology . 2004;101:299–310
  20. Murphy GS , Szokol JW , Marymont JH , et al.   Opioids and cardioprotection (The impact of morphine and fentanyl on recovery of ventricular function after cardiopulmonary bypass) . J Cardiothorac Vasc Anesth . 2006;20:493–502
  21. Law-Koune JD , Raynaud C , Liu N , et al.   Sevoflurane-remifentanil versus propofol-remifentanil anesthesia at a similar bispectral level for off-pump coronary artery surgery (No evidence of reduced myocardial ischemia) . J Cardiothorac Vasc Anesth . 2006;20:484–492
  22. Guarracino F , Landoni G , Tritapepe L , et al.   Myocardial damage prevented by volatile anesthetics (A multicenter randomized controlled study) . J Cardiothorac Vasc Anesth . 2006;20:477–483
  23. Sloth E , Berg H , Jacobsen CJ . The cardioprotective properties of sevoflurane in patients undergoing coronary surgery show some ambiguity when evaluated by clinical outcome . Eur J Anaesthesiol . 2005;22(suppl):18
  24. Garcia C , Julier K , Bestmann L , et al.   Preconditioning with sevoflurane decreases PECAM-1 expression and improves one-year cardiovascular outcome in coronary artery bypass graft surgery . Br J Anaesth . 2005;94:159–165
  25. El Azab SR , Rosseel PMJ , De Lange JJ , et al.   Effect of sevoflurane on the ex vivo secretion of TNF-α during and after coronary artery bypass surgery . Eur J Anaesthesiol . 2003;20:380–384
  26. De Hert SG , Van der Linden PJ , Cromheecke S , et al.   Choice of the primary anesthetic regimen can influence intensive care unit length of stay after coronary surgery with cardiopulmonary bypass . Anesthesiology . 2004;101:9–20

PII: S1053-0770(06)00184-4

doi:10.1053/j.jvca.2006.05.001

Journal of Cardiothoracic and Vascular Anesthesia
Volume 20, Issue 4 , Pages 473-476, August 2006

Article Tools