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The Direct Myocardial Effects of Xenon in the Dog Heart In Vivo

Preckel, Benedikt, MD, DEAA*; Ebel, Dirk, MD; Müllenheim, Jost, MD*; Frädorf, Jan, MD; Thämer, Volker, MD; Schlack, Wolfgang, MD, DEAA*

doi: 10.1097/00000539-200203000-00012
Cardiovascular Anesthesia: Research Report
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Xenon has minimal hemodynamic side effects, but no data are available on its direct myocardial effects in vivo. We examined myocardial function during the global and regional administration of xenon in the dog heart. Anesthetized (midazolam/piritramide) dogs (n = 8) were instrumented for measurement of left ventricular pressure, cardiac output, and blood flow in the left anterior descending coronary artery (LAD) and circumflex coronary artery. Regional myocardial function was assessed by sonomicrometry in the antero-apical and the postero-basal wall. Hemodynamics were recorded during baseline conditions and during inhalation of 50% or 70% xenon, respectively. Subsequently, a bypass containing a membrane oxygenator was installed from the carotid artery to the LAD, allowing xenon administration only to the LAD-dependent myocardium. No changes in myocardial function were observed during inhalation of xenon. The regional administration of 50% xenon had no significant effect on regional myocardial function (systolic wall thickening and mean velocity of systolic wall thickening). Seventy percent xenon reduced systolic wall thickening by 7.2% ± 4.0% and mean velocity of systolic wall thickening by 8.2% ± 4.0% in the LAD-perfused area (P < 0.05). There were no changes of global hemodynamics, coronary blood flow, and regional myocardial function in the circumflex coronary artery-dependent myocardium. Xenon produces a small but consistent direct negative inotropic effect in vivo.

Klinik für *Anaesthesiologie and †Physiologisches Institut I Universitätsklinikum Düsseldorf, Germany

Xenon was provided by Messer Griessheim GmbH, Germany.

November 6, 2001.

Address correspondence and reprint requests to Benedikt Preckel, MD, DEAA, Klinik für Anaesthesiologie Universitätsklinikum Düsseldorf, Postfach 10 10 07, D-40001 Düsseldorf, Germany. Address e-mail to preckel@uni-duesseldorf.de.

Xenon is a noble gas with favorable physical, chemical, and pharmacological properties and can become an adjunct to anesthesia. Several previous studies have focused on its cardiovascular side effects (1–4). In humans, the echocardiographically obtained left ventricular (LV) fractional area change was not altered by 65% xenon (1). No significant effect on arterial blood pressure was observed in patients anesthetized with 70% xenon in comparison to 70% nitrous oxide (3). In pentobarbital anesthetized pigs, cardiac index, central venous pressure, aortic pressure (AOP), and systemic vascular resistance (SVR) were not significantly altered by 30%–70% xenon (5). Seventy percent xenon did not affect heart rate or systolic or diastolic blood pressure in α-chloralose anesthetized dogs (6). The only cardiovascular side effect observed during xenon anesthesia was a tendency for a decreased heart rate accompanied by an increased variability of the cardiac rhythm (1,2,7). In isoflurane-anesthetized dogs, xenon decreased heart rate and increased the time constant of isovolumic relaxation (8).

In all these studies, xenon was inhaled, allowing no differentiation between global hemodynamic and direct myocardial effects. One recent study investigated the direct myocardial effects of xenon in isolated guinea pig hearts and myocytes and showed that the inert gas does not alter cardiac function or major cardiac cation currents (9). The present study is the first to investigate direct cardiac effects after the regional myocardial administration of xenon in vivo.

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Materials and Methods

Experimental procedures complied with the Guiding Principles in the Care and Use of Animals as approved by the Council of the American Physiologic Society and with the German Law on Protection of Animals. The protocol was approved by the bioethical committee of the District of Düsseldorf.

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Animal Preparation

Beagle dogs of either sex (weight range, 16.5–21.0 kg) were anesthetized with IV sodium thiamylal (20 mg/kg) followed by piritramide (1 mg/kg) and midazolam (1 mg/kg) (piritramide, a 4-amino piperidine derivative, is a synthetic μ-opioid receptor agonist widely used in Europe). After tracheal intubation, ventilation of the lungs was controlled to maintain a Paco2 of approximately 35 mm Hg (Starling pump, Type 874/052, Braun Melsungen, Melsungen, Germany). Anesthesia was maintained with continuous infusions of piritramide (0.4 mg · kg−1 · h−1) and midazolam (0.4 mg · kg−1 · h−1). Additional bolus doses were given when required during the surgical preparation, and 70% nitrous oxide was added during preparation but discontinued at least 30 min before starting the experimental protocol. Adequacy of this anesthesia regimen was demonstrated by lack of muscle movement and hemodynamic responses during surgical preparation. Neuromuscular block during thoracotomy was achieved by vecuronium bromide (0.1 mg/kg) followed by a continuous infusion at 0.05 mg · kg−1 · h−1 during the time of surgical preparation. Fluid loss was replaced by the infusion of normal saline (5 mL · kg−1 · h−1) to maintain the hematocrit within normal limits. The hemoglobin concentration and the hematocrit were 12.5 ± 1.7 g/dL and 40.5% ± 2.1% at the beginning of the experimental protocol and 12.2 ± 1.7 g/dL and 38.1% ± 3.7% at the end of the experimental protocol (P = 0.74–0.81), respectively, showing only small changes of these variables throughout the experiments. Body temperature was maintained at 38°C ± 0.2°C by a heating pad. The aortic pressure was measured using a 3-mm outer diameter Teflon catheter introduced from the right femoral artery and connected to a Statham PD23 pressure transducer (Gould Inc, Cleveland, OH). After a left-sided thoracotomy and pericardiotomy, left ventricular pressure (LVP) was monitored using a catheter tip manometer (Micro-Tip Pressure Transducer, PC-350 A, Millar Instruments, Houston, TX) introduced via the left atrium into the left ventricle. The left anterior descending coronary artery (LAD) and the left circumflex coronary artery (LCX), as well as the pulmonary artery, were dissected free. Metered flowprobes connected to a flowmeter (T208, Transonic Systems Inc, Ithaca, NY) were fitted around the vessels to measure coronary artery blood flow and cardiac output (CO), respectively. Two pairs of ultrasonic crystals (Triton Technology Inc, San Diego, CA) were implanted in both the left antero-apical and the postero-basal wall to assess regional myocardial function. One crystal of each pair was placed in the subendocardium, and the other was epicardially fixed. The ultrasonic signal was monitored on an oscilloscope (Tektronix 453, Tektronix Inc, Beaverton, OR) to verify correct crystal alignment. The left carotid artery was dissected free for later bypass implantation. The dogs received 5000 IU of heparin and 500 mg of acetylsalicylic acid before bypass insertion to prevent bypass thrombosis. Heparin (5000 IU/h) was then given as a continuous infusion for the remaining time of the experiments. After the first part of each experiment, the LAD was occluded proximally, and the bypass was introduced into the distal part of the LAD within 10–30 s. Blood flow through the bypass (LAD flow) was monitored continuously by an inline ultrasonic flowprobe (2N, Transonic Systems Inc). Coronary perfusion pressure of the LAD was measured near the tip of the cannula using the Statham P23 pressure transducer.

The extracorporeal system (Tygon® tubing, 4.0-mm inner diameter, Norton Performance Plastic, Akron, OH) contained a pressurized reservoir heated at 38°C (constant pressure, 80 mm Hg) that served as a source of blood for the LAD. From this reservoir, the blood passed a hollow-fiber oxygenator (Cobe Micros, Cobe Cardiovascular, Arvada, CO) before perfusing the LAD. The oxygenator was supplied with a gas mixture containing 25% O2, 5% CO2, and 70% N2, and the heat exchanger of the oxygenator was used to maintain the blood temperature in the perfusion line at 38°C. For withdrawal of venous blood samples, a catheter (0.8-mm outer diameter) was placed into the interventricular vein, draining myocardium served by the LAD distal to the level of bypass insertion. At specified times, 1-mL samples of systemic or bypass arterial and coronary venous blood were obtained, and myocardial oxygen consumption was calculated applying the Fick principle. The hearts were paced via the left atrium at 20 bpm more than their spontaneous heart rate (120 to 140 bpm; USM 30, Biotronik, Düsseldorf, Germany).

To ensure that even small changes of myocardial function could be determined with the method used, isoflurane, with known myocardial effects, was administered after the xenon measurements had been completed. Isoflurane 0.9 vol.% (corresponding to 0.6 minimal alveolar anesthetic concentration (MAC); equivalent to 70% xenon) was administered using a calibrated vaporizer (Vapor 19.3, Drägerwerk AG, Lübeck, Germany; Datex Capnomac Ultima, Division of Instrumentarium Co, Helsinki, Finland). This concentration was further increased (1.8 vol.%) to demonstrate that dose-dependent changes of the measured variables can be determined with the experimental preparation.

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Experimental Protocol

After the surgical preparation, 30 min were allowed to reach steady-state values, and the experimental protocol was then started.

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Effects of Systemic Xenon Inhalation

The lungs of the dogs were ventilated in a randomized order with a gas mixture containing 50% xenon, 25% O2, and 25% N2 or 70% xenon, 25% O2, and 5% N2 for at least 15 min before measurements were performed. These concentrations correspond to 0.4 and 0.6 MAC of xenon in dogs. The concentration in the breathing system was monitored using a mass spectrometer (Xenotec 2000, Leybold Vakuum GmbH, Köln, Germany). Measurement periods were compared with baseline periods during which the lungs were ventilated with air (fraction of inspired oxygen = 0.25). Between measurements, a 15-min washout time was allowed to ensure that xenon was completely eliminated before the next baseline measurement was performed.

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Regional Myocardial Effects of Xenon

After installing the extracorporeal system, at least 30 min were allowed to reach steady-state conditions. Xenon was then applied exclusively to the LAD-perfused area via the hollow-fiber oxygenator. For this purpose, the oxygenator was gassed in a randomized order with a mixture containing 50% xenon, 25% O2, 5% CO2, and 20% N2 or 70% xenon, 25% O2, and 5% CO2. During baseline periods, a mixture containing 25% O2, 5% CO2, and 70% N2 was used. Measurement periods were compared with baseline periods during installed bypass. Xenon concentration was measured in the gas outlet of the oxygenator. During the regional xenon administration, no relevant xenon concentrations were measured in the breathing system (<5 ± 5 ppm).

Distribution of transmural regional myocardial blood flow (RMBF) to the area perfused by the LAD was measured during baseline conditions and during the regional xenon administration (70%) using colored microspheres (10).

At the end of the experiments, the heart was arrested in diastole by cardioplegic perfusion through the aortic root and the extracorporeal system. After cardioplegic arrest, the LAD area was perfused with 1% dextran in normal saline, whereas the rest of the myocardium was perfused through the aortic root with 0.2% Evans blue added to the same perfusion medium. This treatment identifies the LAD-perfused area as unstained. The mass of this area was determined, and the myocardium was then further processed for determination of RMBF (10).

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Data Analysis and Statistics

LVP and its first derivative, dP/dt, CO, coronary artery blood flow through the LAD and the LCX, and antero-apical and postero-basal myocardial wall thickness were continuously recorded with an ink recorder (Recorder 2800, Gould Inc). The data were digitized using an analog to digital converter (Data Translation, Marlboro, MA) at a sampling rate of 500 Hz and processed on a personal computer.

Global LV function was measured in terms of LV systolic pressure and the maximum rate of pressure increase (dP/dtmax) and decrease (dP/dtmin). Global LV end systole was defined at peak negative dP/dt (11) and LV end diastole as the beginning of the sharp upslope of the LV dP/dt tracing. Systolic time was defined as the time interval from end diastole to end systole.

Regional myocardial systolic function was assessed separately in two regions: (a) in the postero-basal wall (LCX-perfused area), and (b) in the antero-apical wall (LAD-perfused area). Regional end systole was determined as the point of maximal wall thickness within 20 ms before dP/dtmin(12). Regional systolic contractile function was evaluated as systolic wall thickening (sWT, systolic wall excursion as a percentage of end-diastolic wall thickness) and as the mean velocity of sWT (WTmv, systolic wall excursion divided by systolic time). SVR was calculated from the mean arterial blood pressure (MAP) and CO, and coronary vascular resistance was calculated from diastolic aortic pressure and coronary artery blood flow.

All values are expressed as mean ± sem. To investigate the deterioration of hemodynamic measurements during time, paired t-test with Bonferroni correction for repeated interventions was used to compare baseline measurements before bypass or after bypass implantation. Comparison of each baseline with the respective intervention was performed using Student’s t-test for paired observations with Bonferroni correction for repeated interventions. All comparisons were two sided. A probability value of 0.05 or less was considered significant.

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Results

Nine dogs were used; in one dog, recurrent severe arrhythmia occurred during the experiment. Therefore, this dog was excluded from data analysis. Before bypass implantation, no significant changes between baseline measurements were determined. After bypass implantation, only sWT decreased during time from 21.9% ± 2.9% to 20.9% ± 2.9%.

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Global Administration of Xenon

Xenon inhalation had only minimal effects on global hemodynamic variables (Table 1), and only LV dP/dtmax was significantly reduced by both concentrations 5% ± 2% and 9% ± 3%, respectively. No changes in regional myocardial function or coronary artery flow could be observed in either LV areas (Fig. 1).

Table 1

Table 1

Figure 1

Figure 1

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Regional Administration of Xenon via LAD-Bypass

Regional administration of xenon to the LAD-dependent myocardium had no effects on global hemodynamics (LVP, LV dP/dt, CO, MAP, SVR;Table 2). Whereas the administration of 50% xenon had no significant effect on regional myocardial function (sWT was reduced by 2.3% ± 1.6%, P = 0.15; WTmv was reduced by 3.4% ± 1.6%, P = 0.10), 70% xenon reduced sWT by 7.2% ± 4.0% and WTmv by 8.2% ± 4.0% in the LAD-perfused area (both P < 0.05;Fig. 1). No significant effects on coronary blood flow and oxygen consumption in the LAD-dependent myocardium were observed. In the systemically perfused LCX-dependent area, regional myocardial function remained unchanged during regional xenon administration (Fig. 1).

Table 2

Table 2

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Distribution of RMBF During Regional Xenon Administration

Regional blood flow to the epicardial, midcardial, and endocardial layer was 32% ± 1%, 34% ± 1%, and 34% ± 2% of transmural blood flow, respectively. This distribution pattern was not affected by the regional administration of 70% xenon (epicardial, 32% ± 1%; midcardial, 34% ± 1%; endocardial, 33% ± 1%).

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Validation of the Method Using Isoflurane

Inhalation of isoflurane reduced LVP, dP/dtmax, dP/dtmin, and MAP by 5%–27% and depressed regional myocardial function by 4%–22% of baseline values (Table 3). CO remained unchanged.

Table 3

Table 3

During the regional administration of isoflurane, sWT was reduced by 9.7% ± 4.2% and 22.5% ± 6.2% (0.9% and 1.8%), and WTmv was reduced by 11.3% ± 4.3% and 24.3% ± 6.1%, respectively (Table 4). Isoflurane markedly increased LAD flow to 117% of baseline values. The regional isoflurane admini-stration into the LAD bypass influenced neither myocardial function of the LCX-dependent myocardium nor global hemodynamics (Table 4).

Table 4

Table 4

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Discussion

This is the first study to investigate direct myocardial effects of xenon in vivo. The main finding is that xenon has a small but consistent direct negative inotropic effect.

According to several investigations (1–6,8), xenon inhalation has only minimal hemodynamic effects and did not significantly alter CO, MAP, and SVR in the present study. However, a significant reduction of LV dP/dt was observed during xenon inhalation, pro-bably reflecting some negative inotropic effects. Although the data from the previous studies and from the first part of our study suggest that xenon does not substantially alter systemic hemodynamics, it is not possible from these investigations to distinguish the direct effects of xenon on myocardial function from global hemodynamic effects. Therefore, we tested the direct effects of intracoronary administration of xenon in vivo. Our results show that xenon produces small but consistent direct negative inotropic effects (reduced sWT and WTmv;Table 2, Fig. 1). Neither changes in myocardial function of the control region nor alterations of systemic hemodynamics were observed during these interventions, and no relevant concentrations of xenon were measured in the expired gas during the regional administration of xenon. Therefore, the negative inotropic effect is not caused by the deepening of anesthesia, but rather by a direct action at the myocardium. Coronary artery flow is not significantly changed.

With regional intracoronary administration of a substance, very small changes of contractile function can be assessed (13) because the forces generated by the normally contracting adjacent myocardium further reduce the regional wall motion of the depressed myocardium. This augmentation of the regional effect can also be seen with the administration of intracoronary isoflurane, where the effects are more pronounced compared with systemic administration. The changes in regional myocardial function were in the range of 10%–20%, but these changes occurred in only one part of the anterior wall perfused by the bypass, whereas the more proximal region of the LAD-dependent myocardium was still perfused with systemic blood not containing the anesthetic (the bypass was implanted behind the first branch of the LAD). More importantly, the myocardium perfused by the LCX and the right coronary artery was also unaffected by the anesthetics. Therefore, it is not surprising that changes in regional myocardial function in the LAD-dependent area did not affect global LV performance. The effects of xenon appear to be small in comparison with those induced by isoflurane and may be clinically negligible.

Our knowledge of the effects of xenon at the cellular and molecular level is still limited. Recently, Stowe et al. (9) demonstrated that xenon does not alter cardiac function in isolated guinea pig hearts. In isolated cardiomyocytes, the amplitudes of the Na+, L-type Ca2+, and the inward-rectifier K+ channel were not altered by xenon concentrations up to 80%. These data suggest that xenon does not affect the cardiac action potential. Besides these results from Stowe et al. (9), no data are available about cardiac effects of xenon at the cellular level. The administration of xenon during reperfusion after coronary artery occlusion reduced myocardial reperfusion injury in rabbits (14). Similar protective effects of other inhaled anesthetics are related to effects on sarcoplasmic reticulum Ca2+ handling (15). However, the present data only show that xenon has a direct effect at the myocardial level but do not allow an analysis of the underlying mechanism.

We used xenon in concentrations up to 70%. During inhalation of xenon, arterial and venous blood gas analyses were performed to determine myocardial oxygen consumption. No changes in arterial oxygen partial pressure were observed. Therefore, the occurrence of hypoxia during xenon inhalation can be excluded. In addition, Calzia et al. (16) demonstrated that diffusion hypoxia is unlikely to occur during recovery from xenon anesthesia. During the regional administration of xenon, samples of arterial blood were taken from the line perfusing the LAD. Again, no changes of arterial oxygen content during xenon administration were observed. For the measurement of regional oxygen consumption, samples of venous blood had to be taken from the great interventricular vein. Although it is well established that the blood in the interventricular vein drains mainly from LAD-dependent myocardium, there is a small but unpredictable admixture of blood from other myocardial regions. These confounding influences may explain why myocardial function was reduced up to 20% during the regional administration of isoflurane, whereas regional oxygen consumption was unchanged or reduced by 8% in the larger concentration (not reaching statistical significance).

Xenon has the most potent anesthetic capability of the inert gases (17,18). The MAC of xenon varies among species. In dogs, a MAC of 119% has been reported (19). Therefore, anesthesia with xenon in dogs must be supplemented with other anesthetics. We used midazolam/piritramide infusion during the experimental protocol. This anesthetic regimen is suitable to investigate direct myocardial effects of other drugs in vivo(13). It cannot be excluded that with different anesthetic supplements or in other species xenon may have different hemodynamic effects. Another limitation may be the open-chest preparation, which per se might produce some hemodynamic changes. The bypass insertion into the LAD and the use of an external perfusion system afterwards were accompanied by small hemodynamic alterations (decrease of sWT and WTmv from 27.5% ± 2.3% and 12.3 ± 1.0 mm/s before bypass to 21.0% ± 2.9% and 10.6 ± 1.8 mm/s after bypass implantation, respectively). Therefore, it is not possible to compare interventions made before bypass insertion with those made after, and the effects of regional xenon application into the LAD were compared only with baseline measurements during bypass perfusion. The administration of isoflurane at the end of each intervention period showed that the preparation still reflects the well-known negative inotropic effects of isoflurane in this experimental setup, even at the end of the experimental protocol. In conclusion, our results show that xenon produces small direct negative inotropic effects on myocardium in the dog heart in vivo.

The authors thank Elke Hauschildt, André Heinen, and Ralf Rulands for technical assistance.

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