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Anesth Analg 2000;90:1089-1097
© 2000 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

Reduction of Postischemic Contractile Dysfunction of the Isolated Rat Heart by Sevoflurane: Comparison with Halothane

Johan F. Coetzee, MMed (Anes), PhD*, Pieter J. le Roux, MMed (Anes)*, Sonia Genade, BSc{dagger},{ddagger}, and Amanda Lochner, PhD{dagger},{ddagger}

Departments of *Anesthesiology and {dagger}Medical Physiology, University of Stellenbosch Faculty of Medicine; and {ddagger}MRC Experimental Biology Programme, Tygerberg, Republic of South Africa

Address correspondence and reprint requests to Prof. J. F. Coetzee, Department Anesthesiology, Faculty of Medicine, University of Stellenbosch, PO Box 19063, Tygerberg 7505, Republic of South Africa.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Our aims were to evaluate the effect of sevoflurane on postcardioplegic functional recovery of the isolated rat heart including the role of the adenosine triphosphate regulated potassium (KATP) channels and to compare the cardioprotective effects of equipotent concentrations of halothane and sevoflurane. Isolated perfused rat hearts were subjected to 45 or 60 min normothermic cardioplegic arrest and 30 min reperfusion. Sevoflurane (0.9% and 1.7%), halothane (0.4% and 0.8%), or sevoflurane (0.9%) plus glibenclamide (10 µM) (a KATP channel blocker) were administered at different time intervals. Measurements of mechanical activity were made before and after arrest. Function during reperfusion after cardioplegic arrest was significantly depressed in both untreated and treated hearts. However, sevoflurane administered both before and after arrest, or before only, significantly improved functional recovery after 45 min of cardioplegia. This protective effect was abolished by simultaneous administration of glibenclamide, suggesting a role of the KATP channel. Sevoflurane was as effective as halothane in improving postcardioplegic functional performance. After 45 min of arrest, hearts exposed to either anesthetic at both concentrations had a significantly higher work performance on discontinuation of their administration than untreated controls. After 60 min of arrest, neither anesthetic elicited protection.

Implications: In view of the possible significance for volatile anesthetics in cardiac surgery, the effects of sevoflurane and halothane were compared on postcardioplegic recovery of rat hearts. Both anesthetics were equally effective in improving functional recovery after normothermic cardioplegic arrest. Sevoflurane’s beneficial effects were abolished by glibenclamide, suggesting a role for the adenosine triphosphate regulated potassium channel.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Sevoflurane, a fluorinated methyl-isopropyl ether, is characterized by low blood-gas solubility and lack of pungency. These characteristics enable more rapid induction of anesthesia, more precise adjustment of its effects, and faster recovery (1). Like all volatile anesthetics, sevoflurane is a cardiodepressant drug, and various studies have shown that its cardiovascular effects are similar to those of isoflurane (2,3), but less than those induced by halothane (4).

Various studies have shown that anesthetics such as halothane and isoflurane exert protective effects during reperfusion after myocardial ischemia (5,6) or cardioplegic arrest (7,8). Likely mechanisms include prevention of the rise and oscillations in intracellular Ca2+ associated with ischemia and reperfusion (9) and/or activation of the adenosine triphosphate regulated potassium (KATP) channels (10).

In view of the observations that sevoflurane improved functional recovery (11) and reduced infarct size (12) during reperfusion after ischemia, we hypothesized that it also protects against ischemic damage during cardioplegic arrest. In view of the possible significance for sevoflurane in cardiac surgery, the aims of this study were to (i) optimize the time of administration of sevoflurane in perfused rat hearts subjected to 45 min of normothermic cardioplegic arrest; (ii) evaluate the role of the KATP channel in the cardiac effects of sevoflurane; and (iii) compare the effects of sevoflurane with equipotent concentrations of halothane.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The protocol was approved by the institutional ethics committee, and animals were cared for according to national and institutional guidelines. Male Wistar rats (± 230 g) were anesthetized with intraperitoneal pentobarbital (25–30 mg/rat).

After removal, the hearts were arrested in cold Krebs-Henseleit buffer (4°C), mounted (within 30 s) onto an aortic cannula and perfused retrogradely via the aorta with Krebs-Henseleit buffer for 10 min (composition in mmol/L: NaCl 124; KCl 4.93; CaCl2 1.25; MgCl2 1.62; Na2SO4 0.6; KH2PO4 1.23; NaHCO3 26; glucose 10). The perfusate buffer was oxygenated with 95% O2/5% CO2 at 37.5°C. During retrograde perfusion, the left atrium was cannulated to allow perfusion in the working mode. The atrial filling pressure (15 cm H2O) and afterload (100 cm H2O) were kept constant before and after cardioplegia (for detailed description of technique, see Ref. 13).

After 20 min of perfusion in the working mode, the hearts were arrested with St. Thomas solution (temperature: 37.5°C; composition in mmol/L: NaCl 110; KCl 16; CaCl2 · 2H2O 1.2; MgCl2 · 6H2O 16; NaHCO3 10). Initially, administration of the cardioplegic solution was maintained for 3 min (pressure 100 cm H2O) and repeated for 3 min at 30 min cardioplegic arrest. After arrest, the hearts were reperfused retrogradely with Krebs-Henseleit buffer for 10 min, followed by perfusion in the working mode for 20 min. Sevoflurane or halothane was administered before and after cardioplegia, before cardioplegia, or after cardioplegia (Fig. 1), but was not present during cardioplegic arrest. The anesthetics were introduced into the gas supply of the perfusate by using a calibrated vaporizer (Penlon InterMed; Penlon Ltd., Abington, Oxon, UK). The concentration of the anesthetic was monitored continuously by using a calibrated anesthetic monitor (Ohmeda model 5330; Ohmeda, Louisville, CO).



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  		Figure 1. Experimental protocol. Arrows indicate time intervals at which measurements were made.

 
The mechanism of the protective action of sevoflurane was evaluated by perfusion with glibenclamide (10 µM/L) in the presence and absence of 0.9% sevoflurane (Fig. 1). The hearts were perfused retrogradely during administration of glibenclamide through a side-arm into the aortic cannula. Sevoflurane was administered as described above.

Aortic and coronary flows were collected manually, while the aortic pressure and heart rate were monitored by using a pressure transducer (Viggo-spectramed) connected to a computer. Measurements were made before and after arrest as shown in Figure 1. Total work performance (pressure power + kinetic power) developed by the heart was calculated as follows (14): Go


Go


where PSP = peak systolic pressure, A = area of cannula, CO = cardiac output, T = cycle time, {rho} = density of perfusate, Te = ejection time.

At the end of reperfusion, hearts were freeze-clamped with Wollenberger tongs and stored in liquid nitrogen for determination of high energy phosphates (15).

Controls
The hearts were perfused retrogradely for 10 min, followed by 20 min of perfusion in the working mode, subjected to 45 or 60 min of normothermic arrest, followed by 30 min of reperfusion (10 min retrogradely, 20 min working heart).

Sevoflurane
Before and After Arrest.
After 10 min of retrograde and 10 min of working heart perfusion, sevoflurane (0.9% or 1.7%, = 0.5 or 1.0 minimum alveolar anesthetic concentration [MAC]) was administered for 10 min. After 45 or 60 min of normothermic cardioplegic arrest, hearts were reperfused for 30 min (10 min retrogradely and 10 min working heart in the presence of sevoflurane, followed by 10 min perfusion in the working mode in the absence of the anesthetic).

Before Arrest Only.
The perfusion protocol was as described above, except that sevoflurane (0.9%) was only administered for 10 min during perfusion in the working mode before cardioplegia. Reperfusion was as described above, but in the absence of sevoflurane.

After Arrest Only.
The perfusion protocol was as described for "before and after arrest," except that sevoflurane (0.9%) was administered during the first 20 min of reperfusion only.

Sevoflurane and Glibenclamide
Controls.
The hearts were perfused retrogradely for 10 min, followed by 10 min of perfusion in the working mode. Glibenclamide (10 µM) or sevoflurane (0.9%) was administered retrogradely for either 10 min before and 20 min after 45 min of cardioplegic arrest or for 10 min before arrest only.

Before and After Arrest.
The hearts were perfused retrogradely for 10 min, followed by 10 min of working heart perfusion. Sevoflurane (0.9%) and glibenclamide (10 µM) were then administered simultaneously for 10 min during retrograde perfusion. After 45 min of normothermic arrest, the hearts were reperfused retrogradely for 20 min in the presence of sevoflurane and glibenclamide, followed by 10 min of working heart perfusion in the absence of drugs.

Before Arrest.
The perfusion protocol was as described above, except that sevoflurane (0.9%) and glibenclamide (10 µM) were present before cardioplegia only.

Halothane
Before and After Arrest.
The perfusion protocol was similar to that described for sevoflurane. Halothane (0.4% and 0.8%, = 0.5 or 1.0 MAC) was administered before and after 45 or 60 min of normothermic cardioplegia.

Data analysis was performed by using a computer software package (Sigmastat for DOS version 5.0; Jandel Scientific Software, San Rafael, CA). Within-group hemodynamic measurements were evaluated by using repeated measurements analysis of variance (ANOVA) and between-group comparisons were made by using one-way ANOVA. If the data were not normally distributed (Kolmogorov-Smirnov test) and did not have equal variances (Levene Median test), equivalent nonparametric tests were performed by using the Friedman repeated measures ANOVA on ranks and the Kruskal-Wallis ANOVA on ranks. post hoc multiple comparison procedures were performed by using the Student-Newman-Keuls test. An {alpha} value equal to or less than 0.05 was regarded as indicating a significant result.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Optimization of Time of Administration of Sevoflurane
The effects of sevoflurane (0.9%) on postcardioplegic functional recovery were evaluated when it was administered before and after, only before, or only after 45 min of cardioplegia (Fig. 2).



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  		Figure 2. Effects of time of administration of sevoflurane (0.9%) on aorta output and total work performance during reperfusion after cardioplegic arrest. Sevoflurane, administered only during reperfusion, caused total mechanical failure manifested by zero aortic output: these values are therefore not included in the graphs. Data presented as 95% confidence intervals of the mean. Control = pooled data of three groups: before any manipulations (n = 20), No anesthetic = no anesthetic administered before or after cardioplegia (n = 6), S(b&a) = sevoflurane administered before and after cardioplegia (n = 7), S(b) = sevoflurane administered before cardioplegia only (n = 7). Results of analysis of variance: all groups differed from each other (P < 0.05).

 
Because no differences in prearrest mechanical performance were observed in all three groups (measured before administration of sevoflurane), these values were pooled (n = 20). All values (aortic and cardiac output, heart rate, peak systolic pressure, work performance) obtained after arrest were significantly (P < 0.001) less than their corresponding controls, while end diastolic pressure remained unaltered (results not shown). Administration of sevoflurane, either before and after arrest or before only, led to greater values than the control group during reperfusion (P < 0.05). When administered during reperfusion only, sevoflurane caused complete mechanical failure, and measurements were not possible. Sevoflurane had no effect on the significant reduction in dp/dtmax and -dp/dtmin observed during reperfusion (results not shown).

The Effects of Glibenclamide on Sevoflurane-induced Protection
In these experiments, mechanical activity was measured before the administration of glibenclamide (10 µM) or sevoflurane (0.9%) (20 min total perfusion time) and at the end of reperfusion (105 min total perfusion time) after 45 min of normothermic cardioplegic arrest (Fig. 3). The administration of glibenclamide alone either before and after or only before cardioplegic arrest had no effect on functional recovery, and values obtained were similar to those of untreated controls. Simultaneous administration of sevoflurane and glibenclamide either before and after arrest or only before arrest completely abolished sevoflurane’s protective effects: aortic output, peak systolic pressure, and total work performance were significantly less than with sevoflurane alone. Similar results (not shown) were obtained with a combination of 5 µM glibenclamide and 0.9% sevoflurane.



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  		Figure 3. Effects of glibenclamide (10 µM) on sevoflurane (0.9%)-induced protection of reperfusion injury. Data presented as 95% confidence intervals of the mean. Control = pooled data of the seven groups: before any manipulations (n = 44), No anesthetic = no anesthetic administered before or after cardioplegia (n = 6), S(b&a) = sevoflurane administered before and after cardioplegia (n = 6), S(b) = sevoflurane administered before cardioplegia only (n = 6), G(b&a) = glibenclamide administered before and after cardioplegia (n = 6), G(b) = glibenclamide administered before cardioplegia only (n = 6), S+G(b&a) = sevoflurane plus glibenclamide administered before and after cardioplegia (n = 7), S+G(b) = sevoflurane plus glibenclamide administered before cardioplegia only (n = 7). Results of analysis of variance: *Differ from all other groups. **Differ from all other groups except each other. #Differ from no anesthetic and G(b).

 
Recovery After 45 min Normothermic Cardioplegic Arrest: Halothane Versus Sevoflurane
Within Group Comparisons.
Normothermic cardioplegic arrest for 45 min caused a significant decline in all variables of function (aortic output, cardiac output, peak systolic pressure, work performance) after 20 min of reperfusion. Prolongation of reperfusion to 30 min had no further effect (Table 1).


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  		Table 1. Mechanical Performance of Hearts Subjected to 45 min of Normothermic Cardioplegia: Comparison of the Effects of Sevoflurane and Halothane
 
Halothane at 0.4% had no effect on the mechanical performance of the hearts before cardioplegia, while at 0.8% a significant decline in aortic output and work performance was observed. After 10 min of reperfusion with both concentrations of halothane, all variables of functional performance were significantly less than before cardioplegia. Reperfusion for a further 10 min in the absence of the drug (both 0.4% and 0.8%) caused significant increases in all the above variables (except for heart rate with 0.8% halothane and coronary flow with 0.4% halothane). However, despite this increase, values remained lower than those before cardioplegia.

Except for a reduction in heart rate, sevoflurane (0.9%) had no effect on the mechanical performance of hearts before cardioplegia. After 10 min of reperfusion, all variables (except coronary flow with 1.7% sevoflurane) were significantly less than values before cardioplegia. Reperfusion for a further period of 10 min in the absence of sevoflurane, increased aortic output, peak systolic pressure, and total work significantly, compared with values during reperfusion in the presence of the anesthetic. Except for the coronary flow, the values obtained at the end of reperfusion were significantly lower than those observed before cardioplegia.

Between-Group Comparisons.
In contrast to the halothane (0.4%) and sevoflurane groups, halothane (0.8%) decreased aortic output before cardioplegic arrest.

Aortic output after 20 min of reperfusion in the presence of the anesthetic drugs was lowest in the case of 0.8% halothane, whereas sevoflurane (0.9%) had values significantly greater than the other groups.

After 30 min of reperfusion, all hearts previously exposed to either anesthetic at both concentrations exhibited higher aortic output and total work values than the controls. No differences were observed between the halothane and sevoflurane groups.

Tissue High Energy Phosphates
Reperfusion after 45 or 60 min of normothermic cardioplegic arrest was associated with a marked reduction in tissue adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP), while creatine phosphate (CP) values remained unchanged (Table 2). At the end of reperfusion, no differences in tissue ATP, ADP, AMP or CP contents were detected among the five groups studied.


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  		Table 2. Myocardial High Energy Phosphate Contents (µmol/g wet weight) at the End of Reperfusion
 
Recovery After 60 min Normothermic Cardioplegic Arrest: Halothane Versus Sevoflurane
Sixty minutes of normothermic cardioplegic arrest severely impaired functional performance during reperfusion: several of the hearts did not resume contractions when reperfused (three controls and two each of the anesthetic-treated groups). Of the hearts that did resume contractions, only two controls and one in the sevoflurane group produced aortic flow. No significant differences were observed in either functional performance or high energy phosphates among the groups (Table 3).


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  		Table 3. Mechanical Performance of Hearts Subjected to 60 min of Normothermic Cardioplegia: Comparison of the Effects of Sevoflurane and Halothane
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
These findings represent the first demonstration that sevoflurane improves postcardioplegic functional recovery. The results showed that its protection is maximal at 0.5 MAC and is dependent on the time of administration and opening of the KATP channels. The cardioprotective actions of sevoflurane were similar to those of halothane.

Sevoflurane
The significant sevoflurane-induced improvement in functional recovery during reperfusion after cardioplegic arrest confirms the results obtained in ischemic rat hearts (11). The marked improvement in function on withdrawal of sevoflurane is difficult to explain in view of the observation that sevoflurane had no effect on myocardial function before arrest (Table 1). One possibility is that the arrested heart is more sensitive to sevoflurane’s cardiodepressant action. This improvement may be caused by a reduction in ischemic injury during cardioplegic arrest, amelioration of stunning, and/or a reduction in infarct size. Previous studies suggested that both halothane (7) and sevoflurane (12) exerted their beneficial effects during reperfusion only, and it was presumed that this might also occur in the present study. Because sevoflurane, when given only before cardioplegic arrest, improved functional recovery as efficiently as when given both before and after (Fig. 2), this suggests protection against ischemic damage per se but does not eliminate an effect during reperfusion. Because of its lipid solubility sevoflurane may still be present at the onset of reperfusion, causing amelioration of stunning. Although infarct size was not measured in our study, sevoflurane has been shown to limit infarct size (12). When administered during reperfusion only, sevoflurane caused complete mechanical failure; an explanation for this phenomenon is not readily available.

Sevoflurane Versus Halothane
For comparison purposes, hearts were exposed to equipotent partial pressures of halothane and sevoflurane, expressed as multiples of MAC in humans. The MAC in rats is slightly greater than in humans (16), but this is of no consequence because the potency ratios between the anesthetics are equivalent in humans (0.44) and rat (0.42).

Before Cardioplegia
The results confirm the negative inotropic actions of halothane, previously observed in both isolated hearts (7) and cultured neonatal rat ventricular myocytes (4). However, in the latter model, halothane also had the most significant negative chronotropic effect, in contrast to the perfused rat heart where halothane had no effect (Table 1). These conflicting results may indicate differing modes of action on the two experimental preparations. The coronary vasodilatory action of sevoflurane (17) demonstrated in dogs was absent in the isolated perfused rat hearts (Table 1).

During Reperfusion
In the comparative study (Tables 1 and 3), halothane or sevoflurane was administered both before and after cardioplegic arrest, a protocol which does not permit distinction between their effects on ischemic and reperfusion damage. The results obtained showed that both anesthetics caused a significant improvement in functional recovery after 45 minutes of cardioplegic arrest. Both anesthetics exerted maximal protection at 0.5 MAC, confirming previous observations that halothane, as well as possibly other inhaled anesthetics, was effective at small concentrations in this particular experimental model (7,8). The protective effects were time-dependent and absent after 60 minutes of normothermic cardioplegia (Table 3). These findings are probably observed because the myocardium is irreversibly injured at this stage, as reflected by the reduced levels of high energy phosphate in such hearts (Table 2).

In our previous studies, functional recovery was assessed by the response to epinephrine; hearts pretreated with halothane (7), enflurane, or isoflurane (8) produced greater outputs than control untreated hearts on stimulation with epinephrine. Because halothane and sevoflurane potentiate the positive inotropic effects of {alpha}- and ß-adrenergic stimulation by approximately 200% (18,19), it may be argued that the improved outputs previously observed, resulted from halothane’s potentiation of adrenergic stimulation rather than protection against reperfusion injury. However, the improved recovery induced by halothane or sevoflurane in hearts allowed to recover spontaneously (Table 1) confirms that halothane protects against postischemic contractile dysfunction or stunning per se. This was not associated with an increase in tissue high energy phosphate contents, when measured at the end of reperfusion (Table 2). Failure to show an association between tissue high energy phosphate levels at the end of reperfusion and improvement in functional recovery was also observed in our studies with enflurane and isoflurane (8).

Mechanism of Protection
The negative inotropic and chronotropic effects of anesthetics may provide an ATP-sparing mechanism which protects against ischemia. This appears unlikely, because the protection afforded by halothane was not associated with improved high energy phosphate levels at the end of cardioplegia (7). Furthermore, halothane caused greater depression in myocardial function than sevoflurane while their cardioprotective effects were the same. It is more likely that protection results from limiting function as seen during early reperfusion in the presence of the anesthetics.

Should the volatile anesthetics act via ameriolation of stunning, their effects are likely to be mediated by an effect of intracellular Ca2+ and free radical generation (20). The protective effects of halothane have been shown to be associated with inhibition of Ca2+ accumulation after myocardial ischemia and reperfusion (9), possibly via prevention of Ca2+-influx through the voltage-dependent Ca2+ channels (21), which in turn, may result from opening of the KATP channels and shortening of the action potential (22).

The cardioprotective actions of potassium channel openers are well established (23), and these drugs have been shown to be involved in halothane-induced coronary vasodilation (24) as well as isoflurane-induced reduction in infarct size (10,25). The abolition of sevoflurane-induced protection by glibenclamide (Fig. 3) suggests a role for the KATP channels in protection during cardioplegic arrest. Whether this occurs via shortening of the action potential remains to be determined.

In summary, the results obtained show that halothane and sevoflurane are equally protective in the setting of cardioplegia and suggest an application during cardiac surgery, bearing in mind the care which should be exercised when extrapolating from experimental animals to humans.


   Acknowledgments
 
This project was supported by Abbott Laboratories (South Africa) Pty Ltd, the Harry Crossley Foundation, and the South African Medical Research Council.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication January 4, 2000.




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D. Ebel, B. Preckel, A. You, J. Mullenheim, W. Schlack, and V. Thamer
Cardioprotection by sevoflurane against reperfusion injury after cardioplegic arrest in the rat is independent of three types of cardioplegia
Br. J. Anaesth., June 1, 2002; 88(6): 828 - 835.
[Abstract] [Full Text] [PDF]

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 Ann. Thorac. Surg.Home page
B. Pouzet, J.-B. Lecharny, M. Dehoux, S. Paquin, M. Kitakaze, J. Mantz, and P. Menasche
Is there a place for preconditioning during cardiac operations in humans?
Ann. Thorac. Surg., March 1, 2002; 73(3): 843 - 848.
[Abstract] [Full Text] [PDF]

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press