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Meeting Abstracts  |   September 1995
Desflurane Inhibits Hypoxic Pulmonary Vasoconstriction in Isolated Rabbit Lungs
Author Notes
  • (Loer, Scheeren) Resident.
  • (Tarnow) Professor and Chair.
  • Received from the Department of Anesthesiology, Heinrich-Heine-University Dusseldorf. Submitted for publication January 25, 1995. Accepted for publication April 29, 1995.
  • Address reprint requests to Dr. Loer: Department of Anesthesiology, Heinrich-Heine-University, Moorenstrasse 5, D-40225 Dusseldorf, Germany.
Article Information
Meeting Abstracts   |   September 1995
Desflurane Inhibits Hypoxic Pulmonary Vasoconstriction in Isolated Rabbit Lungs
Anesthesiology 9 1995, Vol.83, 552-556.. doi:
Anesthesiology 9 1995, Vol.83, 552-556.. doi:
Methods: Isolated blood-perfused rabbit lungs were randomly allocated to treatment with either desflurane (n = 6) or halothane (n = 6). HPV, defined as an increase in pulmonary arterial pressure (PAP) at constant flow, was elicited by decreasing inspiratory oxygen concentration from 20% to 3% for 4 min. This effect was determined without (control HPV) and with increasing concentrations of the anesthetics (fraction of inspired carbon dioxide kept constant at 4.8 plus/minus 0.2%, perfusate temperature at 37 degrees Celsius, and blood flow at 100 ml *symbol* min sup -1).
Results: Before exposure to the anesthetics, PAP increased by 8.6 plus/minus 1.9 cmH2O for all lungs within 4 min of hypoxia (control PAP for all lungs 19.6 plus/minus 2.5 cmH2O). Desflurane decreased this effect in a concentration-dependent fashion with an ED50of 14.5%, compared with that of halothane, with an ED50of 1.7%.
Conclusions: Assuming that 1 minimum alveolar concentration (MAC) values of desflurane and halothane for rabbits are 8.9% and 1.39%, respectively, this study yields ED50values for the inhibition of HPV of approximately 1.6 MAC for desflurane and 1.2 MAC for halothane (P not statistically significant).
Key words: Anesthetics, volatile: desflurane; halothane. Lung: hypoxic pulmonary vasoconstriction; isolated rabbit lung.
INHALATIONAL anesthetics inhibit hypoxic pulmonary vasoconstriction (HPV) in in vitro animal experiments in a concentration-dependent fashion. [1-3] Whether desflurane, a new volatile agent acts likewise is unknown. Because most other inhalational anesthetics have a half-maximum inhibiting effect (ED50) of HPV within the therapeutic range it is of interest to study whether this applies also to desflurane. We therefore elicited HPV in blood-perfused isolated rabbit lungs ventilated with increasing concentrations of desflurane and halothane.
Materials and Methods
Isolated Lung Preparation
With approval of the Institutional Animal Care and Use Committee adult New Zealand White rabbits (body weight 3.4 plus/minus 0.3 kg, mean plus/minus SD) of either sex were anesthetized with 30 mg *symbol* kg sup -1 pentobarbital sodium intravenously and randomly allocated to the desflurane or halothane group. After tracheostomy, the animals' lungs were ventilated with air at a tidal volume of 10 ml *symbol* kg sup -1 and a rate of 30 min sup -1 (respirator 683, Harvard, South Natick, MA). Heparin (1,000 IU *symbol* kg sup -1) was injected 3 min before the rabbits were rapidly exsanguinated through the carotid artery. After midline sternotomy, the trachea, heart, and lungs were removed en bloc and perfusion cannulas were tied into the pulmonary artery and the left atrium via the left ventricle, with meticulous care taken to avoid pulmonary air embolism during preparation. The rabbit's autologous blood was used to fill the extracorporeal circulation circuit, and perfusion was instituted at a constant flow of 100 ml *symbol* min sup -1, about 30 ml *symbol* min sup -1 *symbol* kg sup -1 body weight (calibrated roller pump 16670, American Optical, Bedford, MA). The perfusate temperature was maintained at 37 degrees Celsius with a water bath, and pH was maintained between 7.35 and 7.45 by the addition of sodium bicarbonate, if necessary. The time from the start of exsanguination to the start of ex situ perfusion was less than 12 min.
After removal of the lungs from the chest they were inflated for a short period with positive pressures to 15 cmH2O until any visible atelectasis had resolved. Thereafter they were ventilated with 5% carbon dioxide in air and a positive end-expiratory pressure of 3 cmH2O maintained by a water seal in the expiratory limb. In preliminary studies we found that carbon dioxide variations of 0.2% around 4.8% and oxygen variations of 2% around 20% during normoxia and 0.1% around 3% during hypoxia had no measurable effects on HPV, so variations within these ranges were allowed. Premixed gases (5% carbon dioxide in air, 5% carbon dioxide and 3% oxygen in nitrogen) were used with flow meter-controlled addition of oxygen or carbon dioxide or both during ventilation with high concentrations of desflurane until the measured gas concentrations were again within the tolerated ranges.
All gases were supplied by Messer Griesheim GmbH (Duisburg, Germany), desflurane by Kabi Pharmacia (Milton Keynes, United Kingdom), and halothane by Hoechst AG (Frankfurt am Main, Germany). Drager (Lubeck, Germany) vaporizers were used to deliver desflurane and halothane, respectively.
Measurements
Pulmonary arterial pressure (PAP), left atrial pressure, and airway pressures were measured continuously with electromanometers (P23 ID, Statham, Gould, Oxnard, CA). The zero reference level for these pressures was chosen at the top of the lung and balanced to atmospheric pressure. Perfusate oxygen and carbon dioxide tensions, pH (CMS 3MK2, Radiometer, Copenhagen, Denmark) and hematocrit (Haematokrit-Zentrifuge, Hettich, Germany) were determined intermittently. Total lung weight was measured by a force transducer (FT 03, Grass Instruments, Quincy, MA). Inspiratory gas concentrations were measured continuously with an anesthetic gas monitor (PM 8050, Drager).
Experiments
The perfused lungs were initially observed for 20 min to establish an isogravimetric state with a PAP of approximately 20 cmH2O. If an isogravimetric state could not be attained experimental results were not used in this study. Left atrial pressure was adjusted above airway pressure (5 cmH2O) at the beginning of the experiments by the height of the venous reservoir to attain zone 3 flow conditions excluding most likely vascular recruitment during increases of PAP.
HPV was elicited by a reduction of inspiratory oxygen concentration from 20% to 3% for 4 min during ventilation without (control HPV) and with randomized concentrations of desflurane (4.5, 9.0, 13.5, and 18.0%) and halothane (1.0, 2.0, and 3.0%). At every new inspiratory concentration of the anesthetics, 10 min was allowed for equilibration. Inspiratory carbon dioxide concentration was kept constant.
ED50values for desflurane and halothane on pulmonary artery pressure increases during hypoxia were determined as the anesthetic concentrations at which 50% of the maximum pressure response to hypoxia during control HPV (absence of anesthetics) occurred.
To evaluate unspecific effects of a time factor, control HPV was induced before and after exposure to the anesthetics so that each lung served as its own control.
Statistics
All data are presented as mean plus/minus SD, unless otherwise indicated. Within both groups, HPV during increasing anesthetics concentrations was compared with control HPV and analyzed by Wilcoxon's signed-rank test. HPV, expressed as a percentage of control HPV, was used to assess ED50values of the dose-response relations in both groups after linear interpolation. Between both groups differences between means of control HPV and ED50values (after linear interpolation for each lung) were analyzed by Wilcoxon's signed-rank test. A P value of less than 0.05 was considered to be statistically significant.
Results
HPV was studied in 12 rabbit lungs, allocated randomly to treatment with desflurane or halothane and perfused with autologous blood (hematocrit 33 plus/minus 1%; pH 7.38 plus/minus 0.02). There were no statistically significant differences between the groups in baseline PAP or the increase in PAP during hypoxia before (preanesthetic) and after administration of the anesthetics (postanesthetic) (Table 1). Furthermore, within the groups, neither of these variables differed between the pre- and postanesthetic periods, so nonspecific time effects can most likely be excluded.
Table 1. Effects of Desflurane and Halothane on Pulmonary Artery Pressure and Hypoxic Pressor Response
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Table 1. Effects of Desflurane and Halothane on Pulmonary Artery Pressure and Hypoxic Pressor Response
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With the institution of hypoxia, PAP increased promptly in both groups and attained a plateau within the hypoxic period of 4 min. One typical time course of the hypoxic response in the absence and presence of increasing concentrations of desflurane is shown in Figure 1. In the absence of desflurane (control HPV), PAP attained a maximum within 2 min and remained constant during hypoxia. With subsequent normoxia this effect faded within 2-4 min. With increasing concentrations of desflurane the maximum effect decreased, but a plateau was reached within 4 min of hypoxia. The same pattern was observed in all experiments. Therefore it appeared justified to use the plateau values to determine the concentration-effect relations for both anesthetics in the individual lungs (Figure 2). With increasing concentrations of desflurane (from 0-18%) and halothane (from 1-3%), HPV decreased. The means of the effects as percentages of control HPV were used to estimate ED50values (Figure 3). Desflurane attenuated HPV in a concentration-dependent fashion, with an ED50of 14.5%. In the halothane group the inhibition of control HPV was observed with an ED50of 1.7%. To compare the two groups, 1 minimum alveolar concentration (MAC) in rabbits was assumed to be 8.9% for desflurane and 1.39% for halothane. [4,5] This approach revealed ED50values of 1.6 MAC for desflurane and 1.2 MAC for halothane. This difference was not statistically significant.
Figure 1. Time course of the increase in pulmonary arterial pressure (Delta PAP) in response to 4 min of hypoxia without (open circles) and with increasing concentrations of desflurane (filled circles, diamonds, squares, asterisks) in one representative example (baseline pulmonary arterial pressure [PAP] 17 cmH2O, perfusion rate 100 ml *symbol* min sup -1). With increasing concentrations of desflurane, PAP response declined, and pressure plateaus were achieved later but within 4 min. PAP returned to baseline within 4 min of normoxia (fraction of inspired oxygen 0.20).
Figure 1. Time course of the increase in pulmonary arterial pressure (Delta PAP) in response to 4 min of hypoxia without (open circles) and with increasing concentrations of desflurane (filled circles, diamonds, squares, asterisks) in one representative example (baseline pulmonary arterial pressure [PAP] 17 cmH2O, perfusion rate 100 ml *symbol* min sup -1). With increasing concentrations of desflurane, PAP response declined, and pressure plateaus were achieved later but within 4 min. PAP returned to baseline within 4 min of normoxia (fraction of inspired oxygen 0.20).
Figure 1. Time course of the increase in pulmonary arterial pressure (Delta PAP) in response to 4 min of hypoxia without (open circles) and with increasing concentrations of desflurane (filled circles, diamonds, squares, asterisks) in one representative example (baseline pulmonary arterial pressure [PAP] 17 cmH2O, perfusion rate 100 ml *symbol* min sup -1). With increasing concentrations of desflurane, PAP response declined, and pressure plateaus were achieved later but within 4 min. PAP returned to baseline within 4 min of normoxia (fraction of inspired oxygen 0.20).
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Figure 2. Concentration-effect relations for desflurane (filled circles) and halothane (open circles). Maximum pressure increases in the pulmonary artery (Delta PAP) of the individual lungs were determined during hypoxia (fraction of inspired oxygen 0.03) for increasing concentrations of the anesthetics. Pulmonary arterial pressure (PAP) under baseline conditions was 19.6 plus/minus 2.5 cmH2O for all lungs. With increasing concentrations of desflurane and halothane Delta PAP decreased.
Figure 2. Concentration-effect relations for desflurane (filled circles) and halothane (open circles). Maximum pressure increases in the pulmonary artery (Delta PAP) of the individual lungs were determined during hypoxia (fraction of inspired oxygen 0.03) for increasing concentrations of the anesthetics. Pulmonary arterial pressure (PAP) under baseline conditions was 19.6 plus/minus 2.5 cmH2O for all lungs. With increasing concentrations of desflurane and halothane Delta PAP decreased.
Figure 2. Concentration-effect relations for desflurane (filled circles) and halothane (open circles). Maximum pressure increases in the pulmonary artery (Delta PAP) of the individual lungs were determined during hypoxia (fraction of inspired oxygen 0.03) for increasing concentrations of the anesthetics. Pulmonary arterial pressure (PAP) under baseline conditions was 19.6 plus/minus 2.5 cmH2O for all lungs. With increasing concentrations of desflurane and halothane Delta PAP decreased.
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Figure 3. Concentration-effect relations for desflurane (filled circles) and halothane (open circles): effect expressed as a percentage of control hypoxic pulmonary vasoconstriction (HPV) (means plus/minus SEM, n = 6). *Significant difference from control HPV, P < 0.05. The half-maximum inhibiting effect (ED50) values were 14.5% for desflurane and 1.6% for halothane. Both are within the range of 1 and 2 MAC, assuming 1 MAC in rabbits to be 8.9% for desflurane and 1.39% for halothane.
Figure 3. Concentration-effect relations for desflurane (filled circles) and halothane (open circles): effect expressed as a percentage of control hypoxic pulmonary vasoconstriction (HPV) (means plus/minus SEM, n = 6). *Significant difference from control HPV, P < 0.05. The half-maximum inhibiting effect (ED50) values were 14.5% for desflurane and 1.6% for halothane. Both are within the range of 1 and 2 MAC, assuming 1 MAC in rabbits to be 8.9% for desflurane and 1.39% for halothane.
Figure 3. Concentration-effect relations for desflurane (filled circles) and halothane (open circles): effect expressed as a percentage of control hypoxic pulmonary vasoconstriction (HPV) (means plus/minus SEM, n = 6). *Significant difference from control HPV, P < 0.05. The half-maximum inhibiting effect (ED50) values were 14.5% for desflurane and 1.6% for halothane. Both are within the range of 1 and 2 MAC, assuming 1 MAC in rabbits to be 8.9% for desflurane and 1.39% for halothane.
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Discussion
HPV is important for regional ventilation-perfusion distribution, diverting pulmonary blood flow from hypoxic to normoxic alveolar regions. [6] Several studies have provided evidence that volatile anesthetics attenuate this local vascular control mechanism. [1-3,7,8] We have shown that desflurane acts likewise in isolated rabbit lungs.
Our experimental design allowed us to examine the direct effects of desflurane and halothane on HPV and to control secondary influences such as pH, carbon dioxide tension in perfusate, and pulmonary blood flow, which have been shown to influence HPV. [9] To ensure that perfusate and thus oxygen tension in the pulmonary artery had little effect on alveolar oxygen tension during HPV, lungs were ventilated at about ten times the rate at which they were perfused. Because red blood cells play a crucial role in maintaining vascular reactivity to hypoxia, [10,11] we perfused the lungs with autologous blood at normal hematocrit (33%) for rabbits.
Desflurane as well as halothane inhibited HPV in a concentration-dependent manner. We found ED50values of 14.5% for desflurane and 1.7% for halothane. Assuming the rabbit's MAC of desflurane to be 8.9% [4] and 1.39% for halothane, [5] this reveals similar ED sub 50 values for desflurane and halothane of 1.6 and 1.2 MAC, respectively, both ED50values being within the clinical range of 1-2 MAC.
Marshall et al. [1] investigated the effects of anesthetics on HPV in isolated rat lungs and found ED50values of 0.47 MAC for halothane, 0.60 MAC for isoflurane, and 0.56 MAC for enflurane. These authors concluded that halogenated volatile anesthetics inhibit HPV with almost the same potency. The lower ED50value for halothane compared with that in our study may be due to differences in species (rats vs. rabbits), perfusate (heterologous vs. autologous blood), hematocrit (18.5 vs. 33%), and lung perfusion (zone II vs. zone III).
Another study in isolated rabbit lungs (Japanese white) [2] found ED50values of 0.85 MAC for isoflurane and 1.0 MAC for sevoflurane with perfusion under zone II conditions using autologous blood (hematocrit 10%). An in vivo study in dogs [7] revealed an ED50value for isoflurane of 2.4%. Apparently, in addition to the investigated anesthetic and the species, study conditions (in vivo vs. isolated lung; hematocrit; and lung perfusion conditions) play a crucial role when HPV is investigated.
In summary, we have shown that desflurane inhibits HPV in blood-perfused rabbit lungs in a dose-dependent fashion, with 50% inhibition occurring at a concentration of 14.5%, representing about 1.6 MAC.
The authors thank Professor J. O. Arndt for providing laboratory space, intellectual and technical support, and thoughtful review of the manuscript. They appreciate the technical support of Birgitt Berke and thank Kabi Pharmacia (Milton Keynes, United Kingdom) for supplying desflurane.
REFERENCES
Marshall C, Lindgren L, Marshall BE: Effects of halothane, enflurane, and isoflurane on hypoxic pulmonary vasoconstriction in rat lungs in vitro. ANESTHESIOLOGY 60:304-308, 1984.
Ishibe Y, Gui X, Uno H, Shiokawa Y, Umeda T, Suekana K: Effect of sevoflurane on hypoxic pulmonary vasoconstriction in the perfused rabbit lung. ANESTHESIOLOGY 79:1348-1353, 1993.
Sykes MK, Davies DM, Loh L, Jastrzebski J, Chakrabarti MK: The effect of methoxyflurane on pulmonary vascular resistance and hypoxic pulmonary vasoconstriction in the isolated perfused cat lung. Br J Anaesth 48:191-194, 1976.
Doorley BM, Waters SJ, Terrell RC, Robinson JL: MAC of I-653 in beagle dogs and New Zealand white rabbits. ANESTHESIOLOGY 69: 89-91, 1988.
Drummond JC: MAC for halothane, enflurane, and isoflurane in the New Zealand white rabbit: And a test for the validity of MAC determinations. ANESTHESIOLOGY 62:336-338, 1985.
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Domino KB, Borowec L, Alexander CM, Williams JJ, Chen L, Marshall C, Marshall BE: Influence of isoflurane on hypoxic pulmonary vasoconstriction in dogs. ANESTHESIOLOGY 64:423-429, 1986.
Bjertnaes LJ, Hauge A, Nakken KF, Bredesen JE: Hypoxic pulmonary vasoconstriction: Inhibition due to anaesthesia. Acta Physiol Scand 96:283-285, 1976.
Marshall C, Lindgren L, Marshall BE: Metabolic and respiratory hydrogen ion effects on hypoxic pulmonary vasoconstriction. J Appl Physiol 57:545-550, 1984.
Hakim TS, Malik AB: Hypoxic vasoconstriction in blood and plasma perfused lungs. Respir Physiol 72:109-122, 1988.
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Figure 1. Time course of the increase in pulmonary arterial pressure (Delta PAP) in response to 4 min of hypoxia without (open circles) and with increasing concentrations of desflurane (filled circles, diamonds, squares, asterisks) in one representative example (baseline pulmonary arterial pressure [PAP] 17 cmH2O, perfusion rate 100 ml *symbol* min sup -1). With increasing concentrations of desflurane, PAP response declined, and pressure plateaus were achieved later but within 4 min. PAP returned to baseline within 4 min of normoxia (fraction of inspired oxygen 0.20).
Figure 1. Time course of the increase in pulmonary arterial pressure (Delta PAP) in response to 4 min of hypoxia without (open circles) and with increasing concentrations of desflurane (filled circles, diamonds, squares, asterisks) in one representative example (baseline pulmonary arterial pressure [PAP] 17 cmH2O, perfusion rate 100 ml *symbol* min sup -1). With increasing concentrations of desflurane, PAP response declined, and pressure plateaus were achieved later but within 4 min. PAP returned to baseline within 4 min of normoxia (fraction of inspired oxygen 0.20).
Figure 1. Time course of the increase in pulmonary arterial pressure (Delta PAP) in response to 4 min of hypoxia without (open circles) and with increasing concentrations of desflurane (filled circles, diamonds, squares, asterisks) in one representative example (baseline pulmonary arterial pressure [PAP] 17 cmH2O, perfusion rate 100 ml *symbol* min sup -1). With increasing concentrations of desflurane, PAP response declined, and pressure plateaus were achieved later but within 4 min. PAP returned to baseline within 4 min of normoxia (fraction of inspired oxygen 0.20).
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Figure 2. Concentration-effect relations for desflurane (filled circles) and halothane (open circles). Maximum pressure increases in the pulmonary artery (Delta PAP) of the individual lungs were determined during hypoxia (fraction of inspired oxygen 0.03) for increasing concentrations of the anesthetics. Pulmonary arterial pressure (PAP) under baseline conditions was 19.6 plus/minus 2.5 cmH2O for all lungs. With increasing concentrations of desflurane and halothane Delta PAP decreased.
Figure 2. Concentration-effect relations for desflurane (filled circles) and halothane (open circles). Maximum pressure increases in the pulmonary artery (Delta PAP) of the individual lungs were determined during hypoxia (fraction of inspired oxygen 0.03) for increasing concentrations of the anesthetics. Pulmonary arterial pressure (PAP) under baseline conditions was 19.6 plus/minus 2.5 cmH2O for all lungs. With increasing concentrations of desflurane and halothane Delta PAP decreased.
Figure 2. Concentration-effect relations for desflurane (filled circles) and halothane (open circles). Maximum pressure increases in the pulmonary artery (Delta PAP) of the individual lungs were determined during hypoxia (fraction of inspired oxygen 0.03) for increasing concentrations of the anesthetics. Pulmonary arterial pressure (PAP) under baseline conditions was 19.6 plus/minus 2.5 cmH2O for all lungs. With increasing concentrations of desflurane and halothane Delta PAP decreased.
×
Figure 3. Concentration-effect relations for desflurane (filled circles) and halothane (open circles): effect expressed as a percentage of control hypoxic pulmonary vasoconstriction (HPV) (means plus/minus SEM, n = 6). *Significant difference from control HPV, P < 0.05. The half-maximum inhibiting effect (ED50) values were 14.5% for desflurane and 1.6% for halothane. Both are within the range of 1 and 2 MAC, assuming 1 MAC in rabbits to be 8.9% for desflurane and 1.39% for halothane.
Figure 3. Concentration-effect relations for desflurane (filled circles) and halothane (open circles): effect expressed as a percentage of control hypoxic pulmonary vasoconstriction (HPV) (means plus/minus SEM, n = 6). *Significant difference from control HPV, P < 0.05. The half-maximum inhibiting effect (ED50) values were 14.5% for desflurane and 1.6% for halothane. Both are within the range of 1 and 2 MAC, assuming 1 MAC in rabbits to be 8.9% for desflurane and 1.39% for halothane.
Figure 3. Concentration-effect relations for desflurane (filled circles) and halothane (open circles): effect expressed as a percentage of control hypoxic pulmonary vasoconstriction (HPV) (means plus/minus SEM, n = 6). *Significant difference from control HPV, P < 0.05. The half-maximum inhibiting effect (ED50) values were 14.5% for desflurane and 1.6% for halothane. Both are within the range of 1 and 2 MAC, assuming 1 MAC in rabbits to be 8.9% for desflurane and 1.39% for halothane.
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Table 1. Effects of Desflurane and Halothane on Pulmonary Artery Pressure and Hypoxic Pressor Response
Image not available
Table 1. Effects of Desflurane and Halothane on Pulmonary Artery Pressure and Hypoxic Pressor Response
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