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CARDIOVASCULAR ANESTHESIOLOGY

The Effect of Xenon Anesthesia on the Size of Experimental Myocardial Infarction

From the Klinik fuer Anaesthesiologie, University Clinic, Aachen, Germany.

Address correspondence and reprint requests to Dr. Jan-H. Baumert, DEAA, CAIO Anesthesiologie, UMC St. Radboud, Geert Grooteplein 10, Postbus 9101, Nijmegen 6500 HB, Netherlands. Address e-mail to jan.baumert{at}googlemail.com.

Abstract

BACKGROUND: Volatile anesthetics protect the myocardium from ischemia reperfusion damage. Our hypothesis for this study was that xenon reduces the size of myocardial infarction similar in extent to the reduction associated with ischemic preconditioning.

METHODS: Thirty-six pigs weighing 30–35 kg were anesthetized with thiopental and then randomized into four groups: control (myocardial ischemia only), ischemic preconditioning (five 5-min episodes of intermittent myocardial ischemia), xenon preconditioning (three 10-min exposures to xenon 70% followed by myocardial ischemia), and xenon anesthesia (xenon 70%, continued before and after myocardial ischemia). Myocardial ischemia was induced by placing a tourniquet around the left anterior descending coronary artery for 60 min followed by 2 h of reperfusion. Myocardial infarct size and the area at risk for myocardial infarction were measured by Evans Blue and triphenyl tetrazolium chloride staining, respectively.

RESULTS: Mean (sd) myocardial infarct size was reduced from 64% ± 9% of the area at risk in the control group to 19% ± 12% with ischemic preconditioning (P < 0.001), and to 50% ± 9% with xenon anesthesia (P < 0.05 versus control, P < 0.001 versus ischemic preconditioning). Myocardial infarct size was not reduced with xenon preconditioning compared with the control group (59% ± 11%, P = 0.41).

CONCLUSION: Myocardial infarct size was reduced by ischemic preconditioning but less so by xenon anesthesia. Brief, intermittent exposure to xenon before myocardial ischemia did not reduce myocardial infarct size.

Volatile anesthetics and opioids limit myocardial ischemia/reperfusion damage and, thus, reduce the size of myocardial infarction (1,2). This effect, termed "anesthetic preconditioning" (APC), is similar to the reduction in myocardial infarct size resulting from brief periods of myocardial ischemia (ischemic preconditioning [IP]) (2). APC can be demonstrated when volatile anesthetics or opioids are administered both before and after acute ischemia. Administration of anesthetics for several short intervals, before ischemia (i.e., preconditioning), and during reperfusion (i.e., postconditioning) may have additive myocardial protective effects (3). In contrast to volatile anesthetics, xenon anesthesia (XA) does not impair myocardial contractile function and its use is associated with cardiovascular stability (4), even in patients with impaired cardiac function (5). Experimentally, xenon has no effect on voltage-gated Ca²⁺ and K⁺ channels of human atrial myocytes (6,7), and its use was suggested to enhance myocardial recovery after myocardial ischemia (8). Further, xenon was found to limit myocardial infarct size in the rabbit (9) when administered shortly after myocardial ischemia. Whether xenon use is associated with APC, though, has not been extensively investigated in higher order animals with anatomical and physiological properties more closely resembling humans. In a large animal model, the hypothesis of this study was that xenon reduces the size of myocardial infarction similar in extent to that associated with IP.

METHODS

Induction and Maintenance of Anesthesia
After approval by the Animal Care Committee (Bezirksregierung Koeln, Cologne/Germany), thirty-six 30–35 kg German Landrace pigs were investigated, after physical examination by a veterinarian. After overnight fasting, animals received premedication with an IM injection of azaperone 4 mg/kg. Anesthesia was induced by IV administration of propofol 3 mg/kg. The trachea was intubated, and the lungs were ventilated with 100% oxygen, using a tidal volume of 10 mL/kg and a rate of 18–22 per minute, to keep end-tidal Pco₂ between 36 and 42 mm Hg. Monitoring included an eletrocardiogram, tail pulse oximetry, direct femoral artery pressure, and urine output. An IV infusion of Ringer's solution 15 mL · kg^–1 · h^–1 was given. The animals were not paralyzed, and anesthesia was maintained by a continuous infusion of thiopental, 18 mg · kg^–1 · h^–1.

Surgical Preparation
After anesthesia induction, a pulmonary artery catheter was placed via the internal jugular vein. The catheter provided mixed venous oxygen saturation (SvO₂), continuous cardiac output (CCO), and right ventricular end-diastolic volume (CComboV, model no. 774F75, Edwards Life Sciences, Irvine, CA). Correct placement was verified by obtaining pulmonary artery and occlusion pressure curves. A median sternotomy was then performed and both pleural cavities and the pericardium were opened. The animals were given IV 5000 U of heparin, 1 g of magnesium chloride, and 150 mg of amiodarone over 15 min to prevent cardiac arrhythmias. A 20-gauge polyurethane cannula was inserted into the left ventricular (LV) apex to monitor LV pressure. The left anterior descending (LAD) coronary artery was identified and a tourniquet suture was placed around the artery immediately distal to the first diagonal branch. The animals were covered with an airflow warming blanket (Warm Touch, Mallinckrodt, Sligo/Ireland) to maintain body temperature between 38.5 to 39.5 degrees, and were allowed to recovery for 1 h, with continued thiopental infusion.

Hemodynamic recordings, CCO, and SvO₂ data were transferred from a Datex AS/3 anesthesia monitor and the Vigilance Data Logger (Edwards Life Sciences, Irvine, CA), respectively, to a personal computer after analog to digital data conversion using S/5 Collect software (both by Datex Ohmeda, Helsinki/Finland) with a sampling rate of 100 Hz. Mean values over 5 min of CCO and SvO₂ data were recorded. In addition, arterial blood samples were drawn at each collection point for blood gas analysis.

Protocol
The animals were randomly allocated to the following four groups (nine per group): control group (group C) receiving myocardial ischemia without other interventions; group IP; group XA; and a xenon preconditioning group (group XP). The study design was adopted based on previous studies (Fig. 1) (10). The Fio₂ was reduced to 0.21 in all animals. In group XA, xenon 70% (equal to 0.55 minimum alveolar anesthetic concentration [MAC]) was started and thiopental infusion dose was reduced to 12 mg · kg^–1 · h^–1 with no further changes in anesthesia until the end of the protocol (note: the closed-loop circuit always contains some remaining nitrogen). In group IP, IP was induced by five consecutive LAD occlusions. Effectiveness of occlusion was verified by the sudden onset of epicardial cyanosis and anterior myocardial wall akinesia corresponding to the perfusion area of the distal LAD. Each occlusion lasted 5 min and was followed by a 5 min reperfusion, confirmed by the immediate recurrence of normal epicardial color. The intervention lasted 50 min and has been previously shown to produce ischemic preconditioning in dogs (2,11). In group XP, the animals received inhaled xenon 70% for 10 min, followed by a washout until no more xenon was detected in the breathing circuit. The same washin and washout of xenon 70% was repeated twice, each after a 10 min period of no xenon. Animals in groups C, IP, and XP were then ventilated with an Fio₂ of 0.21 in air (Fig. 1). The LAD was occluded for 60 min in all groups. In groups IP and XP, the LAD was occluded 10 min after completion of the interventions. Thereafter, the tourniquet was released to allow for 120 min of reperfusion. Reperfusion was visually confirmed by the appearance of epicardial hyperemia.

View larger version (10K): [in this window] [in a new window]   Figure 1. Diagram showing study design for the four study groups: Continuous xenon anesthesia (70% vol) in the xenon anesthesia group (XA, gray); 3, 10 min washin periods of xenon (70%) in the xenon preconditioning group (XP, gray bars); 5, 5 min left anterior descending (LAD) occlusions in the ischemic preconditioning group (IP, black bars).

Determination of Infarct Size
After final data collection, the LAD was occluded, and 40 mL of Evans Blue solution was injected into the left atrial appendage to stain normally perfused myocardium. Immediately thereafter, 20 mEq of potassium chloride solution was injected at the same site to induce cardiac arrest. The ascending aorta was then cross-clamped, the atria opened, and the tourniquet released. Thirty milliliters of 1% triphenyl tetrazolium chloride solution was injected into the aortic root for determining myocardial area at risk (AR) for infarction. After 15 min of incubation, the heart was resected and the LV immediately cut into six 6–8 mm slices starting 5 mm from the apex and perpendicular to the long axis. The slices were placed on a clear plastic board with the basal face of each slice facing the board. Photographs of each LV section were processed (post hoc analysis with blinding to the type of intervention) to divide each transection into three color areas of blue (unaffected myocardium), red (noninfarcted AR), or gray (infarcted area), before performing computerized planimetry (ImageJ 1.34 software, NIH public domain, USA). The respective areas for each color from all six sections were normalized to the total sum of areas. The size of the myocardial AR, as related to total area, and the myocardial infarction size (IS) in relation to AR were calculated as follows:

Statistical Analysis
The primary end-point of the study was myocardial IS in relation to the AR. Secondary end-points were LV maximum systolic (dP/dt_max) and minimum diastolic (dP/dt_min) pressure changes, LV end-diastolic pressure (LVEDP), heart rate, mean arterial blood pressure (MAP), mean pulmonary artery pressure, and CO. Data collection was performed at baseline and at four consecutive points of time:1) after 1 h of anesthetic administration or APC; 2) at the end of 60 min of LAD occlusion; 3) after 1 h of reperfusion; and 4) after 2 h of reperfusion.

Power calculations assumed that a 20% reduction in myocardial IS with IP would be clinically relevant. A sample size of eight animals in each group provided a power of 0.8 and an of 0.05 assuming a standard deviation of 15%–20%. To compensate for possible dropouts, nine animals were investigated with each protocol.

Myocardial IS was compared among groups using one-way ANOVA, with Bonferroni's post hoc test for multiple comparisons. Hemodynamic data were analyzed using two-way ANOVA, again with Bonferroni's post hoc test for between-group comparison (GraphPad Prism 4.03 software, San Diego/CA). P < 0.05 was regarded significant.

RESULTS

Five animals were excluded from the analysis; three because of failed myocardial staining (one in group C and two in group XP), and two because of coronary thrombosis precluding reperfusion (one in group C and one in group XA). Thus, results are reported for seven animals in groups C and XP, eight in group XA, and nine in group IP. The AR for myocardial infarction as related to total LV area was 42% ± 5%, 39% ± 2%, 48% ± 5%, and 43% ± 8% in groups C, XA, XP, and IP, respectively. This was not different among groups. Myocardial IS after 2 h of reperfusion versus the AR is shown in Figure 2. IP reduced IS compared with the controls (19% ± 12% vs 64% ± 9%, P < 0.0001). Myocardial IS in group XA (50% ± 9%) was reduced compared with the control (P < 0.05) but it was larger than in group IP (P < 0.001). XP had no effect on IS (59% ± 11%) compared with the control group (P = 0.41), and IS was larger than in group IP (P < 0.0001).

View larger version (22K): [in this window] [in a new window]   Figure 2. Myocardial infarct size (IS) in relation to area at risk (AR). Means and sd for n = 7 (control and xenon preconditioning group XP), n = 8 (xenon anesthesia group XA), n = 9 (ischemic preconditioning group IP); **P < 0.001 versus control, *P < 0.05 versus control; ANOVA, Bonferroni's post hoc test.

Hemodynamics data were not changed significantly by administration of xenon or by IP (Table 1). Myocardial ischemia and reperfusion induced tachycardia and moderate decreases in MAP and maximum systolic pressure increase (dP/dt_max), and decreased the velocity of diastolic pressure decline (dP/dt_min). These global effects of ischemia/reperfusion were significant, but there were no differences among groups. LVEDP increased from baseline during ischemia only in group C, but it recovered early during reperfusion. LVEDP values at the beginning of reperfusion were significantly different between group C and each intervention group (group C versus group IP, P < 0.01; group C versus groups XA and XP, P < 0.001). Oxygenation, ventilation, and acid–base balance were not different among groups and did not change significantly from baseline (Table 2). During the first 10 min of reperfusion, electrical cardioversion because of sustained ventricular tachycardia was necessary in eight animals, with equal distribution over the groups. There was no further need for interventions to stop arrhythmia or support circulation.

DISCUSSION

Myocardial IS as produced by LAD occlusion was reduced from 64% ± 9% of the AR in group C to 19% ± 12% with IP, and to 50% ± 9% with XA. XP did not result in a reduction in IS compared with group C (59% ± 11%). Myocardial IS in the XA (P < 0.001) and the XP (P < 0.001) groups were significantly larger than found with IP. Thus, xenon had a limited effect on limiting myocardial IS in pigs, and only when administered continuously during myocardial ischemia and reperfusion. Global hemodynamics was only slightly different among groups, but xenon may have reduced an ischemic increase in LVEDP.

Myocardial preconditioning by anesthetics has been described under various circumstances. Myocardial damage is reduced with continuous administration of a volatile anesthetic during ischemia and reperfusion (12,13), but also if the volatile anesthetic is administered intermittently before sustained ischemia (14–17). APC also confers some late protection, 24–72 h after administration (18). It has been shown that various techniques had some protective effect, but the involved mechanisms have not been completely clarified. There is evidence that APC may produce additional protection after IPC probably via opening of adenosine triphosphate-sensitive potassium channels (19), the apparent end-target of a signaling cascade involved in any preconditioning effect (3,10). Earlier stages of this cascade include induction of protein kinase C subtypes and p38 mitogen-activated protein kinase (MAPK) (14,20–22).

Our results showing that myocardial IP reduces the size (IS) of subsequent myocardial infarction are in accordance with several reports using comparable experimental methods, mostly comparing IP to the volatile anesthetic isoflurane (2,12,15,17,23,24). Reported differences in IS from studies using volatile anesthetics can partly be attributed to species differences in myocardial structure and coronary collateralization. While dogs have a well collateralized coronary system, producing experimental IS between 30% (control) and 10%–15% (IPC as well as APC) of the AR (2) pigs, like humans, lack this extensive collateralization. Typical IS in pig experiments range from 45% (APC) to >60% without protection (25,27). There is only one study in pigs evaluating the mechanisms of IPC. This study reported reduced IS but failed to show an association between reduction in IS and MAPK induction by IPC (25), which has been proven in a rat model (26). The importance of species differences is further supported by a recent report showing that ischemic postconditioning did not reduce IS in a pig model (27). In contrast, postconditioning has been proven effective in rabbit and rat models (28,29).

The primary aim of our study was to investigate the possible myocardial protective effects of XA in a model that more closely resembles potential clinical use. Continuous exposure to xenon in this model would combine a possible preconditioning effect with protection during ischemia and reperfusion injury. To further evaluate the potential role of XP only, we included a group that was intermittently exposed to xenon before induction of myocardial ischemia/ infarction. Our results show that the protective effect of XA for reducing IS was significantly less than that of IPC and was only found if xenon was administered during ischemia and reperfusion. Preckel et al. (9) reported similar results, finding limited protection (IS 39% vs 51% with xenon and control, respectively; P < 0.05) by administering xenon during reperfusion in an in vivo rabbit model. On the other hand, in rats xenon was found to reduce IS, from 51% to <30%, a protective effect identical to IPC as well as APC with isoflurane (20). There are no other studies directly comparing IPC and APC in pigs.

In this study, thiopental was infused continuously to maintain anesthesia. Thiopental infusion has been used successfully in similar experiments and appears to have only small effects, if any, on myocardial ischemia reperfusion damage (30). The thiopental dose was reduced only in the XA group to obtain comparable anesthetic depth. It cannot be excluded, though, that anesthesia depth was greater in this group, but the similar hemodynamics throughout the surgical procedure among groups suggest that differences in anesthetic depth, if any, would be minimal.

Hemodynamic responses during ischemia and reperfusion were characterized by tachycardia, mild reduction in diastolic function and CO, and limited changes in dP/dt_max and MAP in all groups. It is important to note that acute ischemia and reperfusion of about one-third of LV mass in this model did not substantially compromise global LV function. Furthermore, none of the hemodynamic changes was related to the extent of myocardial infarction. The only difference among groups was that xenon appeared to prevent an increase in LVEDP that was found in the control group.

Several limitations to our study must be acknowledged. First, our failure to demonstrate myocardial protection with XP might reflect insufficient xenon dose (approximately 0.55 MAC) to induce true APC. Although APC has been demonstrated with volatile anesthetic concentrations as low as 0.25 MAC (15), it cannot be excluded that a higher xenon dose (impossible under normobaric conditions) might have been effective. Second, because of its low blood solubility, xenon is removed more completely by a 10-min washout period compared with volatile anesthetics. The washout phase used in similar studies of volatile anesthetics, for example, is often 10 min or less (3,10,24). Anesthetics are thus likely to be present in the myocardium when myocardial ischemia is induced, in contrast to XP in our model. However, a reduction in IS has also been demonstrated after several hours of anesthetic washout, suggesting that the presence of residual anesthetics in the myocardium has minimal, if any, effect on true APC (18). Still, differences to other reports might be caused by their less complete washout of xenon (20). The third limitation of our study is the absence of biochemical data, which could have clarified the mechanism of myocardial protection. As induction of MAPK is not found in connection with IPC in pigs (25), no conclusions can be drawn from studies in which MAPK activation was shown to be part of the protective mechanism.

In conclusion, in a pig model, we found that myocardial IS was reduced by IPC but less so by XA. Brief, intermittent exposure to xenon prior to myocardial ischemia did not lead to a reduction in myocardial IS.

Footnotes

Accepted for publication July 19, 2007.

Supported by Deutsche Forschungsgemeinschaft (Fund No. Ro 2000/6-1) and Air Liquide Deutschland GmbH.

The authors declare that there has been no conflict of interest.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Baumert, J.-H Articles by Rossaint, R. Search for Related Content PubMed PubMed Citation Articles by Baumert, J.-H Articles by Rossaint, R. Related Collections Cardiovascular Heart Pharmacology