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Original Article

Isoflurane preconditioning-induced cardio-protection in patients undergoing coronary artery bypass grafting

Lee, M. C.*; Chen, C. H.*,†; Kuo, M. C.*; Kang, P. L.; Lo, A.; Liu, K.*

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European Journal of Anaesthesiology: October 2006 - Volume 23 - Issue 10 - p 841-847
doi: 10.1017/S0265021506000354

Abstract

Introduction

Myocardial stunning is ubiquitous after cardiopulmonary bypass (CPB) in cardiac surgery. Despite marked improvement in surgical techniques and cardioplegic solutions, up to 90% of patients undergoing coronary artery bypass grafting (CABG) experienced decreased ejection fractions and/or cardiac index (CI) postoperatively [1]. Moreover, the overall mortality exceeds 30% in patients with acute ischaemic syndrome, advanced age and decreased myocardial reserve [2]. The significance of myocardial dysfunction is believed to be associated with impaired high-energy production and utilization, inadequate myocardial perfusion, free radical injury and altered calcium homeostasis [3]. In the hope of preventing postoperative ventricular dysfunction and improving overall outcome, recent advances in caring for high-risk cardiac patients centre upon optimization of cardio-protection by introducing cardiac preconditioning as a synergistic adjunct to current strategies.

Ischaemic preconditioning (IPC) as originally described by Murry is defined as a rapid, adaptive response to a brief ischaemic insult that improves the tolerance of the myocardium to a subsequent period of more prolonged ischaemia [4]. Experimental evidence accumulated to date show that IPC helps better preserve the myocardial energy state, delays onset of irreversible cell injury, limits infarct size and induces better recovery of contractile function and fewer reperfusion dysrhythmia [5–9]. Although the precise mechanism of IPC is not clearly defined, the development of brief oxidative stress presumably leads to adaptive modification of the heart through a chain of reactions including generation of intracellular mediators [10], activation of signal transducers [11] and modification of gene expression [12,13].

More recently, extensive research focuses on identifying clinical compounds that could pharmacologically mimic the cardio-protective effects of IPC to avoid an ischaemic-type preconditioning stimulus in high-risk patients in whom any additional myocardial ischaemic injury can adversely affect postoperative outcome. Isoflurane is a popular and widely used volatile anaesthetic among patients undergoing surgical procedures. Many researchers have shown that volatile anaesthetics can exert early preconditioning to reduce myocardial infarction through a signal transduction pathway that is remarkably similar to that observed during IPC [14,15]. Activation of adenosine receptors [16], protein kinase C [17], inhibitory guanine regulatory proteins [18] and mitochondrial and sarcolemmal adenosine triphosphate regulated potassium (KATP) channels [19] are implicated in anaesthetic-induced preconditioning. Experimental studies demonstrate that volatile anaesthetic, when administered immediately before an ischaemic interval, decreases high-energy phosphate utilization during ischaemia, preserves cellular ultrastructure, and improves recovery of postischaemic myocardial contractility [20,21]. Whether these experimental approaches will yield reproducible clinical benefits in patients with stunned myocardium remains to be determined.

In the present study, we investigated the phenomenon of preconditioning the myocardium with isoflurane to determine whether or not its cardio-protective effects during the ischaemic-reperfusion period result in reduced myocardial dysfunction or infarct after CPB. It is our belief that administering isoflurane via the CPB circuit before aortic cross-clamping is an important adjunct to our current cardioplegic technique, representing an important and clinically accessible component of myocardial protection.

Methods

After approval by the institutional review committee and written informed consent were obtained from the patients, 40 patients with stable angina and multi-vessel disease undergoing elective CABG surgery were enrolled in this prospective, randomized, placebo-controlled study. Patients with acute (<1 week) myocardial infarction, unstable angina, left ventricular aneurysm or very poor left ventricular function (ejection fraction = 25%), significant valvular disease, chronic obstructive pulmonary disease, advanced renal or hepatic dysfunction and those taking sulphonylurea anti-diabetic drugs or theophylline preparations were excluded from participation. Patients' medications were continued up to the morning of surgery.

Anaesthesia and surgical procedures

The conduction of anaesthesia and surgery were similar in all patients. For induction of anaesthesia, a standard protocol with diazepam (0.2 mg kg−1), fentanyl (5–10 μg kg−1), and pancuronium (0.2 mg kg−1) was used. After intubation, all patients were ventilated with a mixture of air and oxygen; but no volatile anaesthetics were administered until the onset of CPB in patients selected for treatment. Anaesthesia was maintained with fentanyl (3–5 μg kg−1 h−1), propofol (2–6 μg kg−1 h−1), midazolam (0.1 μg kg−1 h−1) and pancuronium (40 μg kg−1 h−1). A pulmonary artery catheter was placed after induction of anaesthesia. Following mid-sternotomy and routine preparation, CPB (non-pulsatile roller pump, membrane oxygenator and arterial line filter) was started under full heparinization.

Preconditioning protocol

The CPB circuit was primed with Ringer's lactate (20 mL kg−1), sodium bicarbonate (1 mL kg−1, 7.5% w/v), and mannitol (20% w/v, 5g kg−1). Once bypass was running at a full flow (2.4L min−1 m−2) with the heart depressed, patients were randomly assigned to the control or volatile isoflurane preconditioning groups (ISO group). In the ISO group, isoflurane (2.5 minimum alveolar concentration (MAC)) was added to the gas mixture in the oxygenator for 15 min, followed by 5 min of isoflurane-free bypass before aortic cross-clamping. Patients experiencing severe hypotension (mean arterial pressure < 50 mmHg) after isoflurane administration were excluded to keep away from the possible effect of IPC. Patients in the control group received a time-matched (20 min) period of isoflurane-free CPB. After aortic cross-clamping, modified St Thomas cardioplegic was delivered via the aortic root and coronary sinus to achieve cardiac arrest. The cardioplegic was administered at regular intervals to maintain cardioplegia until completion of the bypass graft.

The core body temperature was allowed to drift to moderate hypothermia of 28–29°C. After completion of vessel anastomosis, the final warming cardioplegic was infused before removal of the aortic cross-clamp, and the heart resumed beating. While the institutional CPB weaning practice was a renal dose of dopamine (2 μg kg−1 min−1), an increased dopamine dose of 5 μg kg−1 min−1 was used when the CI 10 min after termination of CPB was below 2.0 L min−1 m−2.

Determination of biochemistry markers

Blood samples for troponin I (TnI) were obtained before induction of anaesthesia and at 6 h, 1 and 2 days postoperatively. All the ischaemic markers were immediately measured using the Immulite analyser (Turbo, DPC, Los Angeles, CA, USA), using a sandwich chemiluminescence detection method.

Assessment of cardiac function

Using a continuous cardiac output (CCO) monitoring system (Baxter Swan-Ganz® CCO/SVO2 model 744H-7.5F; Baxter/Edwards Critical-Care, Irvine, CA, USA), haemodynamic parameters, including heart rate (HR), MAP, central venous pressure (CVP), mean pulmonary arterial pressure (MPAP), pulmonary capillary wedge pressure (PCWP), CI, stroke volume index (SVI) and systemic and pulmonary vascular resistance indices (SVRI, PVRI) were recorded after anaesthetic induction, 15 min after cessation of CPB, 6 h after arrival in the intensive care unit (ICU), and on the first postoperative day. The variables were measured in triplicate by individuals who were unaware of intraoperative isoflurane administration.

Perioperative pharmacological inotropic support

Administration of high-dose dopamine for post-CPB inotropic support was recorded after CPB completion and 24 h after surgery in the ICU by independent observers blinded to the study protocol.

Clinical outcome analysis

After surgery, patients were evaluated daily for the occurrence of adverse events, such as new myocardial infarction, cerebrovascular insult or renal dysfunction, which were diagnosed by the intensive care physician who were not aware of the objective or the hypothesis of the study. Long-term end-points, including length of stay in ICU, length of hospital stay and the time requirement of extubation were also recorded.

Statistical analyses

All data are expressed as means ± SDs. Patient characteristics and CPB data were analysed using χ2 (or Fisher's exact test) and unpaired t-tests. U-test was used to analyse the differences in the serial TnI data between the two groups of patients. Differences in serial haemodynamic profiles, both within the same group and between groups were analysed using paired t-tests or analysis of variance for repeated measures. Significance was set at P < 0.05. Statistical analyses were performed using the SPSS statistical software package, version 10.0 (SPSS Inc., Chicago, IL, USA).

Results

Salient patient characteristics and the intraoperative data are summarized in Table 1. The study groups were similar with respect to all parameters before CPB. Complete revascularization and uneventful surgery was achieved for all patients.

Table 1
Table 1:
Patient characteristics and operation data.

Haemodynamics

MAP and HR increased after surgery. The changes in HR, MAP, CVP, MPAP and PCWP were similar in both groups (Table 2). PVRI was significantly increased after surgery in both groups. In the control group, there was no significant change in CI after CPB. In the ISO group, CI increased significantly from 2.1 ± 0.4 to 2.7 ± 0.7 and 2.6 ± 0.6L min−1 m−2 at 15 min after CPB and 6 h after surgery, respectively (P < 0.05; Table 2). The SVI was significantly higher in the isoflurane group after CPB and 6 h after surgery as compared to the control subjects (P < 0.05).

Table 2
Table 2:
Perioperative haemodynamic data.

Cardiac TnI analysis

The postoperative release of cardiac TnI was consistently lower in the isoflurane group than that in the control group (Fig. 1). The mean TnI level at 24 h after surgery was significantly reduced in the isoflurane group compared with the control group (P = 0.04).

Figure 1.
Figure 1.:
Mean cardiac TnI concentration in the control and ISO groups before surgery (pre-op) and 6, 24 and 48 h after surgery, data are presented as mean ± SD; P = 0.042.

Inotropic support

After CPB, 20% (5/20) of the patients in the control group and 15% (3/20) of the patients in the isoflurane group received high-dose dopamine (>5 μg kg−1 min−1) support. There were no statistical differences between the two groups.

Clinical outcome

There was no adverse effect related to isoflurane administration. Length of stay in ICU, length of hospital stay and time requirement of extubation were not significantly different. Postoperatively, there was one patient death and one patient with pleural effusion in each group.

Discussion

An increasing number of investigations demonstrate that isoflurane protects against myocardial ischaemia-reperfusion injury. The present study showed that 15-min pre-administration of isoflurane followed by a 5-min washout period resulted in an improved post-bypass CI and reduced TnI release in patients undergoing CABG surgery.

IPC of the myocardium is a proven alternative and powerful cardio-protective strategy. Two distinct windows of protection are produced by IPC: an acute early memory phase limited to 1–3 h after the brief ischaemic stimulus (termed classic preconditioning) [22], and a longer, more delayed, period emerging after 12–24 h and persisting for up to 72 h (termed second-window preconditioning) [23,24].

Volatile anaesthetics, including isoflurane, provided myocardial protection in experimental animals through a signal transduction cascade that is remarkably similar to the pathways identified in IPC [25–28]. Pre-administration of isoflurane exerted a protective effect by reducing infarct size when the discontinuation of this volatile agent was followed by a washout period before ischaemia. A few small studies have investigated the anaesthetic-induced preconditioning effect of isoflurane in patients undergoing CABG surgery and the data support a cardio-protective effect of isoflurane as evidenced by a trend of consistently lower levels of creatine kinase (CK-MB) and TnI, improved haemodynamic recovery and decreased ST-segment changes [29–31].

Myocardial ischaemia and reperfusion result in dysrhythmia, injury to coronary microvasculature and contractile dysfunction or myocardial stunning. Myocardial stunning after CABG is associated with increased morbidity and mortality in patients with severe multivessel disease and with reduced myocardial function. Previous studies demonstrated that CI remains essentially unchanged or is even lowered immediately after CABG [32]. This contractile dysfunction usually resolved within 24–48 h and it did not appear to be dependent on alterations in preload and afterload [33]. Warltier and colleagues showed that isoflurane improved the functional recovery of stunned myocardium [34]. Our results are in concordance with the findings that isoflurane-pretreated patients had improved recovery of myocardial performance postoperatively, as manifested by better CI and SVI during the first 15 min and 6 h after CPB (P < 0.05). Due to the preload of the heart, manifested as PCWP and CVP, were similar between the groups, the haemodynamic improvement might result from less stunned myocardial function and better recovery of contractility. While CI can be influenced by many other therapeutic interventions, especially inotropic support, because there was no statistically significant difference in post-CPB dopamine support between the groups, this potential source of influence was minimal.

Whether isoflurane is capable of producing second-window preconditioning remains unclear. Kehl and colleagues [35] demonstrated that isoflurane did not produce a second window of protection when administered 24 h before prolonged myocardial ischaemia in vivo. In agreement with their findings, we found that the changes in CI 24 h after CPB did not significantly differ, suggesting that isoflurane did not confer delayed preconditioning protection in CABG patients. Conversely, Tanaka and colleagues [36] demonstrated that exposure to isoflurane 24 h before coronary artery occlusion and reperfusion reduced experimental myocardial infarct size in rabbits, indicating a second window of preconditioning. The discrepancy may be due to variations in experimental design and more likely resulted because the late window of protection seems to occur at distinct times in different species [37]. Future research is needed to characterize the time and duration of the early and second windows of anaesthetic-induced preconditioning.

We used TnI, a sensitive marker of cellular necrosis, to evaluate myocardial cellular injury in our study. Unlike the myocardial fraction of CK-MB, it is not released from skeletal muscle during surgery and is normally present in the plasma in very low concentrations, thus providing a wide diagnostic window. The results showed consistently lower release of TnI in the ISO group. Compared to the controls, the mean TnI level was significantly reduced in the ISO group at 24 h after surgery. Our results support the improved myocardial protection that isoflurane confers, as demonstrated by previous studies [29,30].

We acknowledge several potential limitations of the present study. Firstly, patients taking sulfonylurea anti-diabetic drugs were excluded because previous studies proved oral hypoglycaemic agents are inhibitors of the KATP channel, and both ischaemic and anaesthetic preconditioning are abolished by sulfonylurea [38,39]. Due to coronary artery disease and myocardial infarction occur with increased frequencies among diabetic patients, preconditioning of the diabetic myocardium may differ considerably from preconditioning of non-diabetic myocardium. The role of isoflurane-induced preconditioning in diabetic hearts needs to be thoroughly investigated before any conclusion can be drawn as to its applicability in the clinical situation. Secondly, the present study only examined the effects of isoflurane at 2.5 MAC in one cycle therefore we could not show dose-related effects of isoflurane during CABG. Furthermore, despite several cycles of IPC being shown to improve outcome compared to only one cycle [40], it remains to be established whether or not anaesthetic preconditioning can be enhanced by administering the volatile anaesthetic in several cycles of exposure interspersed with corresponding washout intervals. It may also be severely constrained by practical considerations to allow enough time for sufficient washout to occur in vivo during anaesthesia and surgery. Thirdly, different anaesthesia protocols could change the results. Nonetheless, in our study, the two groups underwent the same anaesthesia protocol, thus minimizing the potential influence of differing protocols. Fourthly, the CI and SVI differences are rather short-lived, suggesting only an early protective effect of isoflurane-induced preconditioning. Larger scale studies are required to validate these findings and to determine whether isoflurane could confer a longer protection at clinically relevant concentrations. Finally, owing to cost and practical considerations, it is hard for us to increase our sample size. A small sample size may have low statistical power, introduce important biases and the results may not be robust. Further investigation with a larger sample size will be required to determine how isoflurane preconditioning can be best achieved in the clinical setting.

In summary, the current results indicate that a 15-min pre-administration of isoflurane (2.5 MAC), followed by a 5-min washout period before aortic cross-clamping appeared to confer significantly early improvement in haemodynamic performance and significantly reduced release of TnI of human beings hearts after CABG. Further studies are needed to investigate how anaesthetic preconditioning can be best achieved in the clinical setting.

Acknowledgement

This work has been supported by a research grant from the Kaohsiung Veterans General Hospital (VGHKS 93-01).

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Keywords:

ISCHAEMIC PRECONDITIONING, myocardial; ANAESTHETICS, INHALATIONAL, isoflurane; CARDIOPULMONARY BYPASS

© 2006 European Society of Anaesthesiology