Anesth Analg 2003;97:1353-1359
© 2003 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
Thiamylal and Pentobarbital Have Opposite Effects on Human Platelet Aggregation In Vitro
Masami Sato, MD*,
Hideo Hirakata, MD*,
Takefumi Nakagawa, MD
,
Kyoko Arai, MD
, and
Kazuhiko Fukuda, MD*
Departments of *Anesthesia and
Orthopedic Surgery, Kyoto University Hospital, Kyoto; and
Department of Anesthesia, Shizuoka City Hospital, Shizuoka, Japan
Address correspondence and reprint requests to Hideo Hirakata, MD, Department of Anesthesia, Kyoto University Hospital, Sakyo-ku, Kyoto, 606-8507, Japan. Address e-mail to hirakata{at}kuhp kyoto-u.ac.jp.
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Abstract
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The effects of barbiturates on human platelet function are not fully understood. We designed the present study to clarify the effects of thiamylal and pentobarbital on human platelet aggregation and to elucidate the underlying mechanisms in vitro. Human platelet aggregation induced by adenosine diphosphate (ADP), epinephrine, arachidonic acid (AA), and (+)-9,11-epithia-11,12-methano-thromboxane A2 (STA2), measured with an 8-channel light transmission aggregometer, was compared in the absence and presence of thiamylal or pentobarbital. To estimate thromboxane A2 (TXA2) receptor binding affinity, Scatchard analysis was done using [3H]-S145, a specific TXA2 receptor antagonist. STA2-TXA2 receptor binding assay was also examined. The release of AA was determined in platelets preincubated with [3H]-AA and stimulated by ADP, using a liquid scintillation analyzer. Cytosolic free calcium concentration ([Ca2+]i) was measured in fluo-3/AM-loaded platelets using a fluorometer. Thiamylal enhanced, but pentobarbital suppressed, ADP- and epinephrine-induced platelet aggregation, but they did not affect AA- or STA2-induced platelet aggregation. They had no effect on TXA2 receptor binding affinity. Although thiamylal increased and pentobarbital decreased release of [3H]-AA from ADP-stimulated platelets, both barbiturates had no effect on ADP-induced [Ca2+]i increase. We conclude that thiamylal enhances but pentobarbital suppresses human platelet aggregation in vitro. These effects of barbiturates are mediated by altered AA release without affecting [Ca2+]i increase.
IMPLICATIONS: Thiamylal enhances but pentobarbital suppresses human platelet aggregation in vitro. These effects are attributed to altered arachidonic acid release from platelets, possibly by the effects of phospholipase A2, but not secondary to altered cytosolic free calcium concentration.
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Introduction
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Inhibition of platelet function by anesthetics might result in increased bleeding during the perioperative period. Several volatile anesthetics have been demonstrated to inhibit human platelet aggregation in vivo (1,2) and in vitro (3,4). Ketamine has also been shown to inhibit platelet aggregation (5), whereas the effect of propofol on platelet function is still controversial (6,7).
In contrast to other anesthetics, thiopental enhances human platelet aggregation (8,9). In our previous study, thiopental enhanced platelet secondary aggregation induced by adenosine diphosphate (ADP) and epinephrine and this effect was attributed to increased arachidonic acid (AA) release, which possibly occurs secondary to activation of phospholipase A2 (PLA2) (9).
An oxy-barbiturate, pentobarbital, is still used as a sedative and as an anticonvulsant in clinical practice, and more frequently, as an anesthetic in animal experiments. Therefore, information on the effect of pentobarbital on platelet function is needed by physicians and also by researchers engaged in animal studies. Although thio-barbiturates (thiopental and thiamylal) and an oxy-barbiturate (pentobarbital) have similar chemical structure, they have opposite effects on vascular smooth muscle tension (10). We speculated that these thio-barbiturates and oxy-barbiturate might also have opposite effects on platelet aggregation. We therefore undertook this in vitro study to compare the effects of thiamylal and pentobarbital on human platelet aggregation and attempted to clarify the underlying mechanisms.
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Methods
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Platelet Preparation
The study was conducted in accordance with the human research standards of our institutional ethics committee. After informed consent was obtained, venous blood was donated from 30 healthy volunteers who had taken no drugs known to affect platelet aggregation for at least 2 wk. At each donation, 20 mL of venous blood was obtained and was placed into plastic tubes containing 2 mL of 3.8% w/v trisodium citrate. The blood was centrifuged at 160g for 10 min to prepare platelet-rich plasma (PRP) or at 1600g for 30 min to prepare platelet-poor plasma (PPP). The platelet count of the PRP was adjusted to 300,000/mm3 by adding PPP. PRP was used for the aggregation studies and for the measurement of cytosolic free Ca2+ concentration ([Ca2+]i). To prepare washed platelet suspension, a 10% volume of 100 mM EDTA (pH 7.4) was added to PRP and the mixture was centrifuged at 900g for 15 min. The platelet pellet was suspended in buffer A, which contained 8 mM Na2HPO4, 2 mM NaH2PO4, 10 mM EDTA, 5 mM KCl, and 135 mM NaCl (pH 7.2), and then recentrifuged at 900g for 15 min. Finally, the platelet pellet for thromboxane A2 (TXA2) receptor binding affinity measurement and AA release measurement was suspended in buffer B, which contained 25 mM Tris-HCl, 1 mM EGTA, 5 mM MgCl2, and 138 mM NaCl (pH 7.5).
Aggregation Study
PRP was stored at room temperature for 1 h. Five minutes before each aggregation study, aliquots (200 µL) of PRP were placed into 8 siliconized glass tubes, which were kept at 37°C, and stirred continuously for 1 min before and during the experiments. Solutions (0.5–1 µL) of barbiturates (thiamylal; Mitsubishi Pharma Corporation, Osaka, Japan) or pentobarbital (30 µM–1 mM; Nacalai Tesque Company, Kyoto, Japan) or equivalent volume of distilled water (for control) was added directly to each PRP-containing tube 3 min before starting the experiment. Barbiturates had been dissolved and diluted with distilled water into various concentrations to adjust the volume of barbiturates solution added to PRP between 0.5 and 1 µL (<0.5% of total PRP volume). Indomethacin (10 µM) was added for primary aggregation study. We used 10 µM indomethacin to measure the primary aggregation, because a preliminary study showed that this concentration of indomethacin, but not smaller concentrations, completely abolished platelet secondary aggregation. It was in good agreement with the reports that showed 4.9 µM 50% inhibitory concentration value for indomethacin on cyclooxygenase-1 activity (11). Platelet aggregation induced by ADP (Sigma Chemical Company, St. Louis, MO), epinephrine (Daiichi Pharmaceutical, Tokyo, Japan), AA (Nacalai Tesque Company), and a TXA2 analog [(+)-9,11-epithia-11,12-methano-thromboxane A2, STA2] was measured at 37°C by recording the increases in light transmission using an 8-channel aggregometer (MCM Hematracer 212; MC Medical Inc., Tokyo, Japan). The concentration of each aggregating agent was decided to the minimal one to induce infallibly the aggregation to be examined (primary or secondary aggregation). It was because the effects of inhibitors or facilitating agents on platelet aggregation are usually difficult to observe when the concentration of the aggregators are too large. We evaluated the primary aggregation as the first peak that occurred within 3 min after stimulation and the secondary aggregation as the value 7 min after stimulation. Both values were analyzed statistically in percentage, taking the light transmission of PPP as 100%. Four samples from four separate volunteers were tested with all concentrations of each barbiturate.
TXA2 Receptor Binding Assay
Barbiturates (thiamylal or pentobarbital, 1 mM) or distilled water for control study were added directly to test tubes containing 100 µL of washed platelets (1,000,000/mm3) and buffer B (total 200 µL) 10 min before the addition of [3H]-labeled TXA2 receptor antagonist (5Z-7-(3-endo-([ring-4-[3H] phenyl) sulfonylamino-[2.2.1.] bicyclohept-2-exo-yl) heptenoic acid, [3H]-S145). After incubation for 10 min at 37°C, [3H]-S145 (0.1–10 nM) was added to the test tubes and then incubated for 30 min at 37°C. Specific activity of [3H]-S145 was 12.1 Ci/mmol. We obtained a specific binding count by subtracting a nonspecific binding count in the presence of 10 µM S145 from each point. For the analysis of STA2 binding affinity, 100 µL of platelets suspension was added to test tubes containing 1 mM barbiturates or vehicle, various concentrations of STA2 (1 nM–1 µM), and buffer B (total 200 µL). After incubation for 10 min at room temperature, [3H]-S145 (1 nM) was added to the test tubes and then incubated for 30 min at 37°C. After the addition of 5 mL of ice-cold 5 mM Tris-HCl buffer (pH 7.4), each sample was filtered in vacuo through a Whatman GF/C filter and washed 3 times with 5 mL of precooled Tris-HCl buffer. The radioactivity on each filter was determined using a liquid scintillation analyzer (Tri-Carb 1900 CA; Packard Instrument Co., Meriden, CT). Scatchard analysis and calculation of equilibrium dissociation constant (Kd) and maximal concentration of binding sites (Bmax) were performed for each study. For Scatchard analysis study, three separate experiments were performed with samples obtained from three volunteers. (In each of the experiments, samples obtained from the same volunteer were used at all points with all barbiturates.) For STA2 binding affinity study, three samples from three separate volunteers were tested with each barbiturate.
Measurements of AA Release
Bovine serum albumin (1 mg/mL) and 0.5 µCi/mL [3H]-AA (189 Ci/mmol; Perkin Elmer Life Sciences, Inc., Boston, MA) were added to platelet suspension in buffer B, which was then incubated at 37°C for 1 h. The [3H]-AA-loaded platelets were washed 3 times by centrifugation with buffer A to wash away free [3H]-AA, and finally suspended in HEPES buffer, which contained 10 mM HEPES, 145 mM NaCl, 5 mM KCl, 0.5 mM Na2HPO4, and 6 mM glucose (pH 7.5), with indomethacin (10 µM). Indomethacin was added to remove the effects caused by metabolites of AA. The platelet suspension was incubated on ice for 1 h. A few minutes before use, they were warmed to room temperature. The platelet counts were adjusted to 1,000,000/mm3 by adding PPP. The [3H]-AA-loaded platelets were then stimulated by ADP (5 µM) in the presence and absence of thiamylal or pentobarbital (100 µM–1 mM). The ADP concentration in this study was predetermined to 5 µM which was the averaged concentration applied in the aggregation study. It was because we wanted to determine the AA release in the condition similar to that for the aggregation study. Five minutes after stimulation, the reaction was terminated by adding one-tenth volume of ice-cold 100 mM EDTA. The suspension was centrifuged at 10,000g and 4°C for 2 min to separate the platelets from platelet-free plasma, and the [3H]-AA released into the platelet-free plasma was measured using a liquid scintillation analyzer (Tri-Carb 1900 CA; Packard Instrument Co.). Four samples from four separate volunteers were tested with all concentrations of each barbiturate.
Measurements of [Ca2+]i Concentration
A calcium sensitive fluorescent dye, fluo-3/AM (Dojindo Laboratory, Kumamoto, Japan), was added to PRP at a final concentration of 1 µM and incubated for 30 min at 37°C. The platelet count was adjusted to 300,000/mm3 by adding PPP. Three minutes before stimulation, indomethacin (10 µM) and solutions of thiamylal or pentobarbital (300 µM or 1 mM) or equivalent volume of distilled water (for control) were added. Aliquots (1 mL) were placed in a siliconized glass tube, stirred continuously for 1 min, and then stimulated by ADP (5 µM). Fluorescence intensity and platelet aggregation were monitored simultaneously with a fluorometer (CAF-110; Japan Spectroscopic, Tokyo, Japan) as described previously (5,9). Briefly, the fluo-3/AM-loaded PRP was illuminated with a 75-W xenon lamp at the excitation wavelength of 490 nm, and the fluorescence emitted at 540 nm was monitored. At the end of each experiment, the cells were treated with ionomycin (20 µM) or EDTA (20 mM) to obtain maximal and minimal fluorescence, respectively. The luminescent signal was converted to [Ca2+]i by using a fluo-3-Ca2+ dissociation constant of 396 nM as described by Kao et al. (12). Four samples from four separate volunteers were tested with each barbiturate.
Among the calcium-sensitive fluorescent dyes used to measure [Ca2+]i, fura-2/AM is one of the most reliable and commonly used. However, we used fluo-3/AM instead of fura-2/AM, because thiamylal (>300 µM) decreases the transmittance of light with excitation wavelengths used for fura-2/AM (340 and 380 nm), but does not alter the excitation wavelength for fluo-3/AM (490 nm) (13).
Data were analyzed using an unpaired t-test for aggregation study and measurements of [Ca2+]i. For AA release study, data were analyzed using one-way analysis of variance (ANOVA) followed by Scheffé test as a post hoc test. For TXA2 receptor binding assay, Scatchard analysis data were analyzed using one-way ANOVA, whereas for STA2 binding affinity, two-way ANOVA was used. All data except Scatchard analysis were expressed as mean ± SD. Data of Scatchard analysis were expressed as the mean value. Differences at P < 0.05 were considered significant.
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Results
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Thiamylal (300 µM and 1 mM) enhanced secondary aggregation induced by ADP and epinephrine (Fig. 1, A and B), but did not affect primary aggregation induced by ADP (5 µM) or epinephrine (1 µM) (102.9% ± 8.9% and 105.5% ± 9.0% of control value, respectively). In contrast, pentobarbital (300 µM and 1 mM) suppressed secondary aggregation induced by ADP and epinephrine (Fig. 2, A and B), but did not affect primary aggregation induced by ADP (5 µM) or epinephrine (1 µM) (98.9% ± 17.4% and 110.0% ± 7.1% of control value, respectively). Thiamylal and pentobarbital (1 mM, each) did not affect aggregation induced by STA2 (Figs. 1C and 2C ) or AA (1 mM) (97.9% ± 2.4% and 107.8% ± 7.1% of control value, respectively).
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Figure 1. Thiamylal (300 µM and 1 mM) enhanced platelet aggregation induced by (A) adenosine diphosphate (ADP; 4 µM) and (B) epinephrine (0.5 µM), but did not affect aggregation induced by (C) (+)-9,11-epithia-11,12-methano-thromboxane A2 (STA2; 0.5 µM). Data are shown as percent aggregations at 7 min after stimulation. Data are expressed as mean ± SD (n = 4, each). *P < 0.05 versus control.
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Figure 2. Pentobarbital (300 µM and 1 mM) suppressed platelet aggregation induced by (A) adenosine diphosphate (ADP; 6 µM) and (B) epinephrine (1 µM), but did not affect aggregation induced by (C) (+)-9,11-epithia-11,12-methano-thromboxane A2 (STA2; 0.5 µM). Data are shown as percent aggregations at 7 min after stimulation. Data are expressed as mean ± SD (n = 4, each). *P < 0.05 versus control.
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Scatchard analysis of [3H]-S145 binding showed that thiamylal and pentobarbital (1 mM, each) affected neither Kd nor Bmax values (Fig. 3A) (Kd: 0.41 ± 0.018, 0.49 ± 0.061, and 0.47 ± 0.069 nM; Bmax: 25.7 ± 1.0, 25.3 ± 2.7, and 22.8 ± 2.4 fmol/108 platelets; control, thiamylal, and pentobarbital, respectively). Neither thiamylal nor pentobarbital changed STA2 (agonist) binding affinity (Fig. 3B).
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Figure 3. A, Scatchard analysis of [3H]-S145 binding to washed platelets. Thiamylal (1 mM) and pentobarbital (1 mM) affected neither equilibrium dissociation constant (Kd) nor maximal concentration of binding sites (Bmax) significantly. B = bound, F = free. The profile is representative data of three separate experiments (n = 3, each). B, Thiamylal (1 mM) and pentobarbital (1 mM) did not affect (+)-9,11-epithia-11,12-methano-thromboxane A2 (STA2)-thromboxane A2 receptor binding affinity. cpm = counts per minute. Data are expressed as mean ± SD (n = 3, each).
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In the presence of indomethacin (10 µM), ADP (5 µM) increased [3H]-AA release from platelets. Spontaneous [3H]-AA release was subtracted from ADP-stimulated [3H]-AA release in the presence and absence of thiamylal or pentobarbital. Thiamylal (300 µM and 1 mM) enhanced, but pentobarbital (300 µM and 1 mM) suppressed, ADP-induced [3H]-AA release from [3H]-AA loaded platelets (Figs. 4 and 5).
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Figure 4. Thiamylal (300 µM and 1 mM) increased adenosine diphosphate (5 µM)-induced [3H]-arachidonic acid (AA) release from [3H]-AA-loaded platelets in the presence of indomethacin (10 µM). cpm = counts per minute. Data are expressed as mean ± SD (n = 4, each). *P < 0.05 versus control (without thiamylal).
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Figure 5. Pentobarbital (300 µM and 1 mM) suppressed adenosine diphosphate (5 µM)-induced [3H]-arachidonic acid (AA) release from [3H]-AA-loaded platelets in the presence of indomethacin (10 µM). cpm = counts per minute. Data are expressed as mean ± SD (n = 4, each). *P < 0.05 versus control (without pentobarbital).
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ADP (5 µM) produced an increase in [Ca2+]i concomitant with primary aggregation in indomethacin (10 µM)-treated platelets. Thiamylal and pentobarbital (1 mM, each) did not affect the basal level of [Ca2+]i or the ADP-induced increase in [Ca2+]i (Fig. 6).
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Figure 6. Thiamylal and pentobarbital (1 mM, each) did not affect basal or adenosine diphosphate (ADP; 5 µM)-stimulated level of cytosolic calcium concentrations ([Ca2+]i) in indomethacin (10 µM)-treated platelets. Data are expressed as mean ± SD (n = 4, each).
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Discussion
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The binding of weak agonists, such as ADP or epinephrine, to platelets causes primary aggregation and release of AA. Released AA is converted to prostaglandin H2 by cyclooxygenase, and then prostaglandin H2 is converted to TXA2 by TXA2 synthetase. The subsequent activation of TXA2 receptors triggers secondary aggregation; TXA2 receptor activates platelet PLCß, which hydrolyzes phosphatidyl inositol 4,5-bisphosphate and produce inositol 1,4,5-trisphosphate and diacylglycerol. Whereas diacylglycerol activates protein kinase C, inositol 1,4,5-trisphosphate mobilizes Ca2+ from dense tubular systems of platelets.
In the present study, thiamylal (300 µM and 1 mM) enhanced secondary aggregation induced by ADP and epinephrine, whereas pentobarbital (300 µM and 1 mM) suppressed it, but neither altered primary aggregation, suggesting that these barbiturates affected formation or function of TXA2. Moreover, the barbiturates did not alter a TXA2 analog (STA2)- or AA-induced aggregations, strongly suggesting that thiamylal augmented but pentobarbital suppressed TXA2 formation, rather than affected the signaling cascade that follows TXA2 formation. The radioligand-binding assay of TXA2 receptor and STA2-TXA2 receptor binding assay is consistent with this speculation.
The first step of TXA2 formation is AA release from plasma membrane. To determine whether thiamylal or pentobarbital affected the release of AA, we performed an AA release study using [3H]-AA-loaded platelets in the presence of 10 µM indomethacin. We used indomethacin, a cyclooxygenase inhibitor, to avoid the formation of TXA2 that induces further platelet stimulation. The amount of released AA in this condition was therefore much less than that when secondary aggregation occurred. In such an experimental condition, we demonstrated that thiamylal increased but pentobarbital decreased AA release.
Human platelets release AA from membrane phospholipids predominantly through the activity of cytosolic PLA2 (14). The activity of this enzyme is regulated by [Ca2+]i and by serine phosphorylation (15). Calcium-dependent translocation of cytosolic PLA2 to plasma membrane is mediated by an N-terminal C2 domain. This enables the intact enzyme to hydrolyze membrane-resident substrates (16). However, serine phosphorylation of cytosolic PLA2 has been shown to be catalyzed by mitogen-activated protein kinase (MAPK) (15). Initially, two forms of MAPK, extracellular signal-regulated kinase (ERK)1 and ERK2, have been detected in platelets and ERK2 has been shown to be enhanced in thrombin-stimulated platelets (17). It is suggested that p38, another form of MAPK, may contribute to platelet activation (18,19). Dangelmaier et al. (19) showed that ADP caused generation of a certain factor in human platelets to activate p38 kinase, and that this response was mediated by P2Y1 receptor activation.
To determine whether the effects of barbiturates on AA release were caused by altered [Ca2+]i, we evaluated their effects on ADP-induced increase in [Ca2+]i under the condition that secondary aggregation was suppressed by indomethacin. The lack of effects of these barbiturates on [Ca2+]i in the present study suggests that thiamylal enhanced, whereas pentobarbital suppressed, serine phosphorylation of cytosolic PLA2 through interaction with MAPK activity. The possible interactions of thiamylal and pentobarbital with MAPK remain to be clarified in future studies.
Thio-barbiturates, such as thiopental and thiamylal, are barbiturates with sulfur at carbon 2, whereas oxy-barbiturates including pentobarbital have oxygen at this site. The present study revealed that these thio- and oxy-barbiturates have opposite effects on platelet aggregation. Thio-barbiturates have shorter durations of action, shorter latency to onset of activity, and more metabolic degradation than corresponding oxy-barbiturates (20) because of their greater lipid solubility (20,21). Therefore, they are often used for anesthetic induction. We reported that thiopental enhanced ADP- and epinephrine-induced secondary human platelet aggregation by increasing AA release during primary aggregation and also reported that the underlying mechanism of increase in AA release may be calcium-dependent activation of PLA2 (9). Combined with the present results, thio-barbiturates, but not oxy-barbiturates, enhance platelet aggregation by enhanced AA release. However, the mechanism of increased AA release is different between thiopental and thiamylal, because thiopental but not thiamylal augmented increase in [Ca2+]i (9). These facts may suggest that thiopental enhances PLA2 by increase in [Ca2+]i whereas thiamylal enhances PLA2 by a mechanism other than increase in [Ca2+]i.
Philp et al. (8) demonstrated that pentobarbital suppressed ADP-induced human platelet aggregation without alteration of ADP-induced [Ca2+]i increase. These findings are consistent with our results. However, two other studies have shown results apparently inconsistent with ours. Az-ma et al. (22) showed that pentobarbital did not affect collagen-induced aggregation of human platelets. The apparent disagreement of their results from ours can be ascribed to the different mechanisms of platelet activation induced by ADP and collagen. The inconsistency of the other study (23) with ours may be explained by species difference, in addition to different experimental conditions; e.g., they used Quin-2 as a calcium-sensitive fluorescent dye instead of fluo-3/AM and much larger concentrations of barbiturates and ADP than our study. Particularly, platelet responses to ADP are known to be affected by species differences (24).
The peak plasma concentrations of thiamylal and pentobarbital in clinical use are reportedly 150 µM (25,26) and 40 µM (27), respectively, which are smaller than the effective concentrations to alter platelet function shown in the present in vitro study. Barbiturates are used clinically in alkaline solutions. In a preliminary study, we checked the effect of barbiturate solutions on pH of PRP and found that pH-change by 1 mM barbiturates was smaller than 0.05. This effect was smaller than pH-change of PRP during experiments. We determined the effect of supra-clinical concentrations of barbiturates in vitro on platelet aggregation caused by weak agonists. Although the clinical dosage of barbiturates is considerably less than the dosage used in this study, for critically ill patients or for patients with disorders of platelets, the effect of barbiturates on platelet aggregation could influence their physical status. Because we did not incorporate an ex vivo aggregation study, it is hard for us to speculate the duration of these barbiturates on platelet aggregation after administration. Moreover, the half-life values of thiamylal and pentobarbital are 3–8 hours and 20–40 hours, respectively (25,27) but half-life values of blood concentration after single use are much smaller because of redistribution. This problem should be elucidated in further studies.
We conclude that thiamylal enhances and pentobarbital suppresses human platelet aggregation induced by weak agonists in vitro. These effects are attributed to altered AA release from platelets, but not secondary to altered [Ca2+]i.
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Acknowledgments
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This work was supported by departmental funds.
We thank Yoshio Hatano, MD (Professor and Chairman, Department of Anesthesiology, Wakayama Medical College, Wakayama, Japan) and Kumi Nakamura, MD (Chief Anesthesiologist, Kyoto City Hospital, Kyoto, Japan) for their advice during the experiment. We also thank Ono Pharmaceutical (Osaka, Japan) for a gift of (+)-9,11-epithia-11,12-methano-thromboxane A2 (STA2) and Shionogi Research Laboratories (Osaka, Japan) for a gift of 5Z-7-(3-endo-([ring-4-[3H] phenyl) sulfonylamino-[2.2.1.] bicyclohept-2-exo-yl) heptenoic acid ([3H]-S145).
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Footnotes
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Presented in part at the annual meeting of the American Society of Anesthesiologists, Dallas, TX, October 9–13, 1999 and the 8th annual meeting of the European Society of Anaesthesiologists, Vienna, Austria, April 1–4, 2000.
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Accepted for publication June 20, 2003.
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Abstract
Introduction
