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Anesth Analg 2005;100:335-339
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000142118.84049.80

CARDIOVASCULAR ANESTHESIA

The Effects of Xenon or Nitrous Oxide Supplementation on Systemic Oxygenation and Pulmonary Perfusion During One-Lung Ventilation in Pigs

Konrad Schwarzkopf, MD*, Torsten Schreiber, MD*, Elke Gaser, MD*, Niels-Peter Preussler, MD*, Lars Hueter, MD*, Harald Schubert, DVM{dagger}, Helga Rek*, and Waheedullah Karzai, MD{ddagger}

*Department of Anesthesiology and Intensive Care Medicine and {dagger}Institute for Experimental Animals, University of Jena; and {ddagger}Department of Anesthesiology and Intensive Care Medicine, Zentralklinik Bad Berka, Germany

Address correspondence and reprint requests to Konrad Schwarzkopf, MD, Department of Anesthesiology and Intensive Care Medicine, University Hospital, 07740 Jena, Germany. Address e-mail to konrad.schwarzkopf{at}med.uni-jena.de.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
During experimental one-lung ventilation (OLV), the type of anesthesia may alter systemic hemodynamics, lung perfusion, and oxygenation. We studied whether xenon (Xe) or nitrous oxide (N2O) added to propofol anesthesia would affect oxygenation, lung perfusion, and systemic and pulmonary hemodynamics during OLV in a pig model. Nine pigs were anesthetized, tracheally intubated, and mechanically ventilated. After placement of arterial and pulmonary artery catheters, a left-sided double-lumen tube was placed via tracheotomy. IV anesthesia with propofol was supplemented in random order with N2O/O2 60:40 or Xe/O2 60:40 or N2/O2 60:40. All measurements were made after stabilization at each concentration. Differential lung perfusion was measured with colored microspheres. Oxygenation (Pao2: 90 ± 17, 95 ± 20, and 94 ± 20 mm Hg for N2/O2, N2O/O2, and Xe/O2) and left lung perfusion (16% ± 5%, 14% ± 6%, and 18.8% for N2/O2, N2O/O2, and Xe/O2) during OLV did not differ among the 3 groups. However, mean arterial blood pressure (78 ± 25, 62 ± 23, and 66 ± 23 mm Hg for N2/O2, N2O/O2, and Xe/O2) and mixed venous saturation (55% ± 12%, 48% ± 12%, and 50% ± 12% for N2/O2, N2O/O2, and Xe/O2) were reduced during N2O/O2 as compared with the control group (N2/O2). Supplementation of IV anesthesia with Xe or N2O does not impair oxygenation nor alter lung perfusion during experimental OLV.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
The effects of anesthetics on oxygenation during lung collapse or one-lung ventilation (OLV) depends on direct and indirect effects of anesthetics on the perfusion of the nonventilated lung. During OLV, hypoxic pulmonary vasoconstriction (HPV) diverts blood flow from the nonventilated to the ventilated lung, thereby reducing perfusion of the nonventilated lung, decreasing shunt fraction, and ameliorating the decrease in arterial oxygen (O2) tension (Pao2) (1). Direct effects of anesthetics on hypoxic lung perfusion can be shown in in vitro studies where typically volatile anesthetics directly depress HPV in a dose-dependent manner (2–4). Indirect affects of anesthetics on HPV and lung perfusion can be appreciated in in vivo models, where decreases in cardiac output (CO) and decreases in mixed venous oxygenation (Svo2) through volatile anesthetics may strengthen HPV and decrease perfusion in collapsed lung regions (5–7).

An important question related to the use of anesthetics during OLV is, therefore, how direct and indirect effects interact and affect oxygenation and lung perfusion. The properties of the inert gas xenon (Xe) as an almost ideal inhaled anesthetic are well known (8,9). Improvements in the development of fully closed, low-flow anesthetic breathing circuits may reduce the costs of Xe anesthesia so that Xe may become a potential anesthetic, especially in hemodynamically compromised patients who may benefit from the systemic hemodynamic stability provided by Xe anesthesia. Nitrous oxide (N2O) and Xe may be used to supplement volatile or IV anesthesia during lung collapse or OLV requiring higher fractions of oxygen (10). The effect of Xe on HPV and on lung perfusion during regional lung collapse are not well known. In a clinically relevant animal model, we studied how Xe and N2O as supplemental anesthetics affect systemic hemo-dynamics, perfusion of the nonventilated lung, and ox-ygenation during OLV.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The study design was approved by the local Animal Protection Committee and by the governmental Animal Care Office (Landesverwaltungsamt Thueringen, Germany). The study was conducted in animals specifically bred for scientific use and were parasite free (German land race, bred by Charles River Laboratories, Sulzfeld, Germany). After overnight fasting with free access to water, 9 female pigs (25–35 kg) were premedicated with ketamine (500 mg IM) to allow placement of an IV line, pulse oximetry, and continuous electrocardiogram monitoring. General anesthesia was induced with propofol (2–3 mg/kg IV) and rocuronium (0.9–1.2 mg/kg IV). Then the trachea was orally intubated with a 6.5–8.0 ID endotracheal tube. Mechanical ventilation was adjusted during preparation to maintain arterial CO2 tension (Paco2) at approximately 34–40 mm Hg. Anesthesia was maintained with a 1:1 mixture of N2O and O2 and continuous infusions of propofol (20–35 mg · kg–1 · h–1), remifentanil (10–20 µg · kg–1 · h–1), and pancuronium (0.1–0.2 mg · kg–1 · h–1). Using the sterile technique, a femoral arterial catheter was advanced 20–25 cm to be positioned in the abdominal aorta via a 5F percutaneous sheath introducer set for hemodynamic monitoring and arterial blood gas sampling. A flow-directed thermodilution pulmonary artery catheter was passed through a 8.5F introducer through the right external jugular vein. The tip of the pulmonary artery catheter was positioned just beyond the pulmonary valve to ensure placement in the main pulmonary artery (i.e., the catheter was not advanced to the wedge-position). The catheter was connected to a CO device (M-COPSv; Datex, Helsinki, Finland). CO measurements were performed in triplicate with 10 mL of cold saline (1°C–5°C) and averaged for each time point. A central venous catheter was placed in the right internal jugular vein. Subsequently, a tracheotomy was performed, and the orotracheal tube was replaced under fiberoptic control by a left-sided, specially designed 39 Ch double-lumen tube (DLT). This DLT ensured that the right upper bronchus of the pigs could also be ventilated or accessed through the tracheal limb. After DLT placement, the animals were positioned in the left decubitus position, and a 8.5 ID endotracheal tube was passed through a right-sided mini-thoracotomy into the right pleural space. Ventilation to the right lung was then discontinued, and lung collapse was verified by fiberoptic control of the right pleural space via the tube.

During the study, correct DLT placement was verified by continuous dual capnography. Fiberoptic bronchoscopy and thoracoscopy were repeated at the end of each of the three study phases, followed by a recruitment maneuver of the ventilated lung. Recruitment was performed manually with a pressure of approximately 50 cm H2O and duration of 20 s.

After preparation, remifentanil was discontinued, and IV anesthesia was continued with propofol (25 mg · kg–1 · h–1) without changing the dosage throughout the experiment. The lungs of the pigs were ventilated by a closed-system ventilator modified to provide Xe application. We ventilated the pigs in a pressure-control mode at 26–30 cm H2O driving pressure and 5 cm H2O end-expiratory pressure. Ventilation pressures were kept constant during the three phases of the experiment for each pig. Inspired and end-tidal N2O, O2, end-tidal CO2, and Xe were analyzed using the machine-integrated monitor of the PhysioflexTM ventilator (Draeger, Luebeck, Germany). In a crossover design, the pigs were ventilated with N2O/O2 (60:40), Xe/O2 (60:40), and N2/O2 (60:40) in random order. Equilibration times were at least 40 min during each phase. After recording stable cardiorespiratory variables for at least 20 min (no more than 10% variation), respiratory and hemodynamic variables were noted (mean arterial blood pressure [MAP], heart rate, end-tidal CO2 concentration, and O2 saturation via pulse oximetry [all monitoring by Datex, Helsinki, Finland]). Arterial blood and mixed venous blood were analyzed immediately after blood sampling by using an automated blood gas analyzer. At the end of each time period, colored microspheres (see below) were administered over 2 min through a central venous line.

The pigs were kept in the left lateral decubitus position throughout the experiment. Body temperature (38.0°C ± 1°C) was maintained by covering the pigs with a Warmtouch blanket and was continuously monitored by the thermistor of the thermodilution catheter. The pigs received 15 mL/kg of body-warm balanced electrolyte solutions during the induction and preparation, which was continued at a rate of 10 mL · kg–1 · h–1 during the study period.

Application and methodological consideration of microsphere measurements in pigs have been presented and discussed in detail elsewhere (11). Briefly, for measurements of regional pulmonary perfusion, 1.2 x 106 colored microspheres (Dye-Trak, Triton Technology, San Diego, CA) with a nominal diameter of 15 µm and suspended in Tween 80 (Fluka, Neu-Ulm, Germany) were mixed for 3 min by sonification (Transsonic T 310, Bender and Hobein, Singen, Germany) and injected slowly over 120 s via the central venous catheter into the superior vena cava. The injection was followed by flushing the catheter with 10 mL of saline. Microsphere injections were repeated at the end of the three experimental phases using different colored microspheres (white, blue, eosin, orange, and yellow) in random sequence. At the end of the experiment, the pigs were euthanized and the lungs removed, dissected, and digested by placing them in a 4-N concentrated solution of KOH. The right and left lungs were digested separately. To obtain the microspheres, the digested samples were then filtered under vacuum suction through 8-µm pore polyester membranes filters (Costar, Bodenheim, Germany). The microspheres were washed with a 2% Tween 80 solution and subsequently with ethanol. The colored microspheres were quantified by their dye content. The dye was removed from the microspheres by adding 150 µL of dimethylformamide as a solvent. The photometric absorption of each dye solution was determined to be a sphectrophotometer wave length of 190–820 mm. The number of microspheres was calculated using the specific absorbance value of the different dyes. All reference and tissue samples contained >400 microspheres. Percentage of the right lung perfusion was calculated as the microsphere number obtained from right lung divided by the total microsphere number in both lungs.

The data were statistically analyzed by a Friedman statistics, and Wilcoxon signed ranks test was used for comparisons where appropriate. A step-wise linear regression analysis was performed for Pao2 with the factors CO, perfusion of the nonventilated lung, Pvo2, Svo2, type of anesthetic, tidal volume, and maximal airway pressure. Statistical tests were performed with the computing software Statistical Packet for the Social Sciences (SPSS, Chicago, IL). A P value of <0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
During OLV, respiratory frequency, end-tidal CO2, and peak airway pressure remained unchanged throughout the three phases of the study. Tidal volume was significantly smaller and Paco2 significantly higher during Xe anesthesia as compared with the other two groups. The end-tidal/arterial CO2 difference was much larger in the Xe group as compared with other groups (6.8 ± 4.3, 2.1 ± 4.3, and 1.2 ± 3.7 mm Hg for Xe/O2, N2O/O2, and N2/O2; P < 0.01 for Xe/O2 versus N2/O2; P < 0.05 for Xe/O2 versus N2O/O2). Pao2 and perfusion of the nonventilated lung were comparable among groups. MAP (P > 0.05), CO (P = 0.07), and Svo2 (P < 0.05) were reduced during O2/N2O versus O2/N2 (Table 1). Regression analysis identified perfusion of the nonventilated lung as the main determinant of Pao2 (r = –0.64; P < 0.01).


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  		Table 1. The Effects of Xenon or Nitrous Oxide on Hemodynamic Variables, Oxygenation, and Lung Perfusion During One-Lung Ventilation

 


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In our porcine model of OLV, Xe and N2O did not affect lung perfusion or oxygenation during OLV. N2O and Xe led to minimal changes in systemic hemodynamics.

Xe possesses many of the characteristics of an ideal anesthetic (12). It has a low blood-gas partition coefficient, leading to rapid induction and emergence from anesthesia, it is nontoxic and lacks teratogenicity, it produces analgesia, and it is a potent hypnotic. Xe anesthesia is associated with stable hemodynamics because Xe does not produce cardiac depression. New, fully closed breathing circuits are available that make Xe anesthesia feasible. Although many studies address hemodynamic and various respiratory aspects of Xe anesthesia, no study assesses its effects on lung perfusion and oxygenation during lung collapse. In this study, we used OLV as a model of lung collapse and found that 60% Xe does not affect systemic or pulmonary hemodynamics, does not affect perfusion of the collapsed lung, and does not affect oxygenation. Although our study was not designed to report on HPV, the fact that systemic and pulmonary hemodynamics and lung perfusion did not differ between the control and Xe phases suggests that HPV was not affected.

Xe has a higher density and viscosity than N2O or nitrogen (13,14). Resistance to airflow is greater in Xe/O2 mixtures as compared with N2O/O2 or N2/O2. In one study in pigs, the airway resistance during Xe/O2 (70:30) was 4.0 ± 1.7 cm H2O · s–1 · L–1 when compared with N2/O2 (2.6 ± 1.1; P < 0.01) and N2O/O2 (2.9 ± 0.8; P < 0.01) (13). Because of this, using volume-controlled ventilation would have led to an increase in airway pressure, which would have affected lung perfusion. Because our main objective was to study lung perfusion and oxygenation, we chose to use pressure-controlled ventilation that would ensure comparable airway pressures among the three groups. For this reason, tidal volumes are significantly smaller and CO2 significantly higher, albeit within the normal range during Xe anesthesia, as compared with the other two groups. There was no relationship between tidal volume or Paco2 and oxygenation in the regression analysis. This suggests that the reduction in tidal volume did not affect the findings of our study.

How N2O would affect lung perfusion and oxygenation during OLV has not been studied adequately, and early studies suggested an inhibition of HPV through N2O (15,16). We now show that, compared with N2, N2O decreases CO, Svo2, and MAP but does not affect Pao2 or perfusion of the nonventilated lung. The reduction in hemodynamics may be a result of cardiodepressive effects of N2O or a consequence of a deepened level of anesthesia (17). The small but insignificant (P = 0.17) decrease in perfusion of the nonventilated lung may be the result of strengthened HPV through reduced CO and Svo2 (5,18).

One problem with Xe and N2O during OLV is their high minimum alveolar anesthetic concentration (MAC) value that makes it necessary to administer at least 50 vol% to achieve a reasonable anesthetic effect. The MAC of Xe in the pig is approximately 119% (103%–135%), whereas the MAC of N2O is approximately 277% (19,20). Despite this difference in MAC, we used an inspiratory concentration of 60% of these anesthetics during OLV. Using equipotent levels of Xe and N2O would have lead to different levels of fraction of inspire O2, which would have then affected lung perfusion and oxygenation during OLV. Furthermore, our main objective was to study the affects of these gases on lung perfusion and oxygenation, and we felt it was appropriate to use the highest possible concentration compatible with OLV.

This study has a number of limitations. The design of our study does not allow separation of direct and indirect effects of the anesthetics on lung perfusion or oxygenation. The effects of Xe or N2O on HPV cannot be discerned from our results. Furthermore, those who advocate using pure oxygen during OLV may question the need and rationale of supplementing anesthesia with N2O or Xe. A number of studies show that the risk of hypoxemia is reduced while using pure O2 during OLV (21). However, using pure O2 during anesthesia may be associated with postoperative atelectasis (22). Furthermore, the risk of hypoxemia while using 50% O2 may be unfounded. We have shown that using 50% O2 is safe during OLV (23). In conclusion, 60% Xe or N2O did not affect oxygenation nor lung perfusion when administered during propofol anesthesia.

Xenon was generously supplied by Messer Griesheim GmbH, Duisburg, Germany.


   Footnotes
 
Presented, in part, at the 10th Annual Meeting of the European Society of Anaesthesiologists, Nice, France, 2002.

Accepted for publication July 27, 2004.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2005 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press