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Abstract |
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Adhesion of polymorphonuclear neutrophils (PMN) to the coronary endothelium is a crucial step in the development of ischemic myocardial injury. We tested the possible effects of six widely used IV anesthetics on non- and postischemic coronary adhesion of PMN in isolated perfused guinea pig hearts. Hearts (n = 5–11/group) were perfused under conditions of constant coronary flow. After 15 min global warm ischemia, PMN (106) were infused in the second minute of reperfusion. The number of cells reemerging in the coronary effluent within 2 min was expressed as a percentage of the total number of administered PMN. Anesthetics were given 20 min before ischemia and during reperfusion. In addition, the ability of the drugs to influence the oxidative burst reaction of PMN was assessed by measuring luminol-enhanced chemiluminescence in response to 0.1 µM N-formyl-L-methionyl-L-leucyl-L-phenylalanine. Under nonischemic conditions, 26.3% ± 0.5% of the injected PMN did not acutely reemerge from the coronary system. Subjecting the hearts to ischemia augmented retention to 40.0% ± 1.6% (P < 0.05). This postischemic stimulation of adhesion was fully prevented by ketamine (10 µM: 22.8% ± 1.6%, 20 µM: 26.6% ± 0.7%), thiopental (25 µM: 24.0% ± 1.7%, 50 µM: 24.0% ± 1.4%), and midazolam (1.5 µM: 29.0% ± 0.9%, 3 µM: 26.4% ± 1.4%). Propofol also inhibited the augmented postischemic retention at 25 µM (28.7% ± 2.4%). However, 50 µM propofol, etomidate (0.5 and 1 µM), and fentanyl (1 µM) all had no effect. Only thiopental reduced the nonischemic adhesion value (14.0% ± 3.7%). This may be linked to the direct antioxidative action of thiopental (50% reduction in oxidative burst activity). Whereas ketamine, midazolam, and propofol did not significantly influence oxidant production by PMN, etomidate and the lipid solvent Intralipid enhanced the burst reaction. This activating effect of the lipid component could explain the biphasic behavior of propofol emulsion. Despite some possible differences in efficacy, several IV anesthetics may protect the heart from PMN-mediated reperfusion injury.
Implications: Ketamine, thiopental, and midazolam, but not etomodate or fentanyl, reduce postischemic adhesion of neutrophils in the coronary system of isolated perfused guinea pig hearts, suggesting a role in mitigating myocardial reperfusion injury.
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Introduction |
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Patients, particularly those with preexisting cardiovascular diseases, can suffer cardiac ischemic episodes during the administration of anesthesia. Even short (5- to 15-min) ischemic periods may elicit severe cardiac dysfunction, caused not only by ischemia but also by the subsequent reperfusion.
Polymorphonuclear neutrophils (PMN) play an important role in reperfusion injuries (1). Neutrophils bear a large cytotoxic arsenal and, pertinently, accumulate in the myocardium after ischemia and reperfusion (1–3). The exact pathomechanism of myocardial injury after ischemia and reperfusion is unclear, but the cardiotoxicity of PMN-derived oxygen-free radicals is well documented (1–3). Neutrophils cause vascular contraction, endothelial dysfunction, and decreased left ventricular performance (2,3). Raschke et al. (4) demonstrated that postischemic dysfunction can be caused even by small numbers of neutrophils through formation of hypochlorous acid. Regardless of the mode of action, the initial step is the adherence of neutrophils to the coronary endothelium. Accordingly, inhibition of intercellular adhesion attenuates the myocardial injury (3–6).
Halothane, isoflurane, and sevoflurane have been found to inhibit postischemic adhesion of PMN, and there is growing evidence that volatile anesthetics may protect against reperfusion injury (7–10). However, IV anesthetics are controversially discussed or disregarded in this respect (8–11). The influence of these drugs on in vitro PMN functions has been widely investigated (12–14), but the studies focused on the defense afforded by neutrophils against invading bacteria and on depressed immunomodulative function after the long-term administration of the anesthetic compounds. The search for protective or deleterious effects of different IV anesthetics on reperfusion injury could be rewarding, as the right choice of IV anesthetic could additionally improve the outcome of perioperative myocardial ischemic periods. We recently observed marked differences in the behavior of S(+)- and R(-)- ketamine on two postischemic events, intracoronary adhesion of PMN and development of coronary vascular leak (5), supporting clinical use of pure S(+)-ketamine stereoisomer in favor of the racemic mixture.
Our aim was to investigate effects of six widely used IV anesthetics on the postischemic adherence of neutrophils in the intact coronary system of isolated guinea pig hearts. In an additional in vitro assay, we attempted to determine whether the individual effect on the postischemic adherence was related to direct or indirect antioxidative properties of the drug by evaluating the oxidative burst reaction of PMN via luminol-enhanced chemiluminescence.
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Methods |
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Thiopental (Trapanal) was obtained from Byk Gulden (Konstanz, Germany), ketamine (Ketanest) and benzethonium from Parke-Davis (Berlin, Germany), etomidate (Etomidat-Lipuro) and fentanyl (Fentanyl B. Braun) from B. Braun (Melsungen, Germany), propofol (Diprivan) from ICI Pharma (Planckstadt, Germany), and midazolam (Dormicum) from Hoffmann-La Roche (Grenzach-Whylen, Germany). Intralipid originated from Kabi Pharmacia (Uppsala, Sweden). Magnetizable CD 15 antibodies were obtained from Miltenyi Biotech GmbH (Bergisch Gladbach, Germany). Luminol and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) came from Sigma Chemie (Deisenhofen, Germany).
Buffer solutions (Krebs-Henseleit buffer, phosphate-buffered saline (PBS), and tris-buffered Tyrode’s solution, pH 7.4 each) were composed as described previously (5).
We used human neutrophils instead of guinea pig PMN, because this allowed a PMN preparation technique minimizing preactivation (5,7,8). Zahler et al. (15) demonstrated that the adhesion of human PMN in the intact guinea pig coronary system does not differ quantitatively from that of homologous PMN.
Human neutrophils were isolated from venous blood, freshly obtained from five healthy volunteers (5). For anticoagulation, 200 µl 0.1% ethylenediaminetetraacetate was present per 10 mL of blood, and blood was immediately centrifuged for 15 min at 450 g. The buffy coat was removed and incubated for 15 min at 8°C with 20 µL iron-tagged antibodies against the PMN-specific epitope CD 15. The labelled buffy coat was passed through a magnetized column (Mini MACS, Miltenyi GmbH). The labelled cells (PMN) were retained in the magnetized column, unbound cells were washed out with 3 x 600 mL buffer (containing 0.5% bovine serum albumin). After removing the column from the magnetic field, the retained cells were flushed out with 1 mL PBS. These were then washed with 10 mL of PBS solution, centrifuged at 450g for 10 min, and resuspended in Tyrode’s solution. The cell count was determined with a Coulter Counter ZM (Coulter Electronics, Luton, UK), and cells were diluted to a final concentration of 106/mL buffer.
The care of the animals and all experimental procedures were in accordance to German animal protection laws and officially approved by the institutional review board and state authorities (Government of Upper Bavaria).
Hearts were isolated from male guinea pigs (body weight 250–330 g). After cervical dislocation by using a specially designed instrument, median thoracotomy was performed, and the hearts were arrested with cold saline. The aorta was cannulated and the heart retrogradely perfused as a nonworking "Langendorff" preparation with Krebs-Henseleit buffer gassed at 37°C with 94.4% oxygen and 5.6% carbon dioxide. The heart was rapidly excised and the caval, azygos, and pulmonary veins were ligated. A steel cannula was inserted into the pulmonary artery to allow the collection of coronary effluent, issuing from the coronary sinus and passing from the right atrium into the right ventricle. The aortic (and, thus, coronary) perfusion pressure was continuously registered with a pressure transducer (P23 Db; Statham Instruments, Hato Rey, Puerto Rico).
Immediately on cannulation, the hearts were perfused at constant arterial pressure (60 mm Hg) for 10 min to complete the preparation procedure. Perfusion was then continued at constant coronary flow of 5 mL/min for 30 min. Global myocardial ischemia was induced by interrupting the perfusion for 15 min, during which the hearts were immersed in Tyrode’s solution (pH 7.40, 37°C). Reperfusion was started again with 5 mL/min constant flow, lasting for 10 min in all experiments. In the first minute of reper-fusion, coronary effluent was collected for lactate measurement (16), determined with the aid of high-performance liquid chromatography. Beside allowing washout of metabolites, this time is required for hearts to regain regular electrical activity. Furthermore, myocardial production of reactive oxygen species is highest during the first minutes of reoxygenation. This is one of the main mechanisms contributing to acute enhancement of PMN adhesion (4,6). Accordingly, it was not until the second minute of reperfusion that a 1-mL bolus of PMN (106 cells in 1 mL Tyrode’s solution) was infused for 60 s into the coronary system via the aortic cannula by an infusion pump (Infors AG, Basel, Switzerland). During this specific time interval, the coronary flow rate totaled 6 mL/min. Coronary effluent was collected continuously during the bolus administration and in the following 60 s to count the number of PMN leaving the coronary system (PMN output). Thus, PMN were sampled for 120 s. Previous studies in our laboratory have shown that only a negligible number of additional PMN emerges in the following 5 min (15). Immediately before intracoronary application, a test bolus was collected from the same syringe (1 mL, 60 s, no coronary passage) to determine the number of cells applied (PMN input). The percentage of PMN retained in the heart was, accordingly, expressed by the following formula: 
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In time-matched control experiments, the neutrophils were applied without previous ischemia: PMN application occurred at the 46th minute of the experimental protocol, but the hearts were perfused at constant flow (5 mL/min) for the 15-min period otherwise occupied by the ischemic phase of the protocol (for details, see Ref. 5). To avoid any influence of already adherent PMN on PMN of a subsequent bolus or on postischemic heart performance (coronary perfusion pressure, lactate release), a separate heart was prepared for each adhesion experiment. Thus, more than 120 animals were required for the present study.
The therapeutic plasma concentrations of IV anesthetics vary widely but are reported to be approximately 28–57 µM for thiopental (17), 10–50 µM for ketamine (18), 0.3–1 µg/mL for midazolam (19), 0.2–3 µM for etomidate (20), 11–44 µM for propofol (21), and >0.15 µM for fentanyl (22). For the adhesion studies, we chose perfusate concentrations in the respective ranges. All drugs were diluted with distilled water to prepare stock solutions concentrated 100-fold above the desired end concentration (see below). Stock solutions of thiopental, ketamine, midazolam, fentanyl, and benzethonium (vehicle of ketamine) were prepared, divided into 5-mL aliquots, stored frozen at -15°C, and thawed for daily use. Etomidate, propofol, and Intralipid were always freshly prepared. The following drug concentrations (final dilution) were tested: thiopental 25 and 50 µM, midazolam 1.5 and 3 µM, ketamine 10 and 20 µM, etomidate 0.5 and 1 µM, propofol 25 and 50 µM, and fentanyl 1 µM. The stock solutions of drugs were administered into the aortic cannula at a constant flow of 50 µL/min for 20 min before ischemia, interrupted during ischemia, and applied again from the first minute of reperfusion until the end of the experiments.
To assess the oxidative burst reaction of PMN, chemiluminescence measurements were conducted according to the following protocol: 300 µL freshly prepared human PMN in Tyrode’s solution (5 x 105 PMN) were placed in a cuvette with 1 mM luminol (100 µL). Fifty microliters of anesthetics or distilled water (controls) were added to the sample, and the cuvette was placed into a Biolumat chemiluminescence detector (Berthold, Wildbach, Germany). Luminol is able to react with free radicals and oxidants, the reaction leading to photon emission. The PMN were then stimulated with 50 µL FMLP (0.1 µM), a very strong chemoattractant, to initiate the burst reaction. In controls, chemiluminescence peaked within 5 min. The peak values (counts/s) of samples containing anesthetics were compared with the control peak value of each batch of PMN and expressed in percent of the control response. Generally, two concentrations of each anesthetic were used, a lower one as also used in the adhesion experiments, and a higher one in the range cited in the literature for assessing effects on oxidative burst activity.
The results were expressed as mean ± SEM. For comparison among the groups, analysis of variance was first used. If the F test proved to be positive, multiple comparisons were performed with the Student-Newman-Keul’s test. For evaluation of the effects of anesthetics and Intralipid on chemiluminescence induced by FMLP, comparison with the individual control value was performed by using Student’s t-test for paired samples. Statistical evaluation of concentration-response behavior of agents with respect to postischemic adhesion and chemiluminescence was performed by using Student’s t-test for nonpaired samples. This test was also used to compare chemiluminescence in the presence of propofol with that for the corresponding amount of Intralipid. Probability values of P < 0.05 were considered to be significant. For investigation of a possible correlation between intracoronary pressures and adhesion values or lactate release and adhesion values, we applied the Spearman correlation analysis.
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Results |
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Under control conditions (no ischemia, constant coronary flow rate 5 mL/min) 26.3% ± 0.6% of the 106 applied human PMN did not reemerge from the coronary system. As shown in Figure 1A, subjecting the hearts to global warm ischemia lasting 15 min increased the adhesion of neutrophils applied in the second minute of reperfusion to 40.0% ± 1.6% (P < 0.05).
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Thiopental (50 µM), but none of the other drugs tested, reduced PMN adherence under nonischemic, basal conditions. In postischemic hearts, thiopental, ketamine, and midazolam each reduced PMN adhesion to nonischemic control levels (P < 0.05). There were no quantitative differences in action in the tested concentration ranges, i.e., the smallest concentration of drug tested was already maximally effective (Fig. 1A). Benzethonium, the compound present in ketamine solutions, exerted no influence on postischemic adhesion (40.7% ± 0.9%, n = 3, results not shown).
In contrast to the above mentioned anesthetics, neither etomidate nor fentanyl affected the postischemic level of PMN adherence (Fig. 1B). Surprisingly, in the presence of propofol, mean basal adhesion tended to be greater than control level, rising to 34.0% ± 3.0%. However, there was tremendous scatter of individual data within the 11 experiments of this group (range 12%–44%), and the result was not significant. In the 25-µM propofol group, the mean postischemic adhesion was reduced to 26.6% (P < 0.05 versus ischemia, range 20%–44%). With 50 µM propofol, postischemic adherence seemed unchanged on average versus the postischemic control group (37.4% ± 4.4%). Intralipid at 0.44 mg/mL, as in 25 µM propofol emulsion, tended to slightly increase nonischemic adherence (Fig. 1B) and gave rise to the scatter of the individual values. With respect to postischemic PMN adhesion, Intralipid had little (0.44 mg/mL) or no inhibitory effect (0.88 mg/mL). Although the concentration-response effects of etomidate, propofol, and Intralipid shown in Figure 1B are suggestive of a negative relationship (more adhesion at the larger concentration), this trend was statistically nonsignificant.
Coronary perfusion pressures (CPP) in the presence and absence of IV anesthetics are shown in Table 1. Basal preischemic coronary perfusion pressure after 5 min of volume-constant perfusion (10 min of protocol) was approximately 19–24 mm Hg in all groups. After another 20 min of volume-constant perfusion in the absence or presence of drugs, CPP was reassessed. The changes are listed as 
CPP30-10 in Table 1. In hearts without anesthetic, CPP rose by approximately 5 mm Hg and a similar increase occurred during the administration of thiopental, ketamine, and fentanyl. Benzethonium showed no difference to the ketamine CPP at the same time points (data are not shown). Emulsions of etomidate (1 µM) and Intralipid led to higher perfusion pressure, i.e., to vasoconstriction, whereas with propofol and midazolam infusion, CPP remained constant compared with baseline. The absence of constriction in the hearts exposed to propofol plus Intralipid suggests that propofol may itself exert a vasodilatory effect. In accordance with a certain degree of preexisting vasodilation, all hearts, except those treated with propofol, exhibited reactive postischemic vasodilation (compare Columns 2 and 4 of Table 1).
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Because vasoconstriction and vasodilation influence arterial shear stress, correlation tests were performed within groups, relating individual CPP values to the degree of postischemic adhesion. However, there was no significant correlation, either positive or negative, between preischemic CPP and postischemic adhesion of PMN in any group. In the case of postischemic CPP, only the group with 20 µM ketamine exhibited a positive correlation (r = 0.98), i.e., CPP increased with a rising number of adherent PMN.
To determine the extent of ischemic stress, lactate measurements were performed before ischemia and in the first minute of reperfusion. Nonischemic hearts released some lactate (approximately 0.3–0.5 µmoL/min). This increased dramatically during early postischemic washout (approximately 30- to 50-fold), averaging 14.2 ± 1.0 µmoL/min in control hearts. This value was not changed by the tested anesthetics or vehicles at any concentration, except in one case: Intralipid at 0.88 mg/mL concentration increased postischemic lactate release to 21.9 ± 1.9 µmoL/min (P < 0.05 versus control). Postischemic release of lactate was not correlated to either postischemic adhesion of PMN or pre- or postischemic CPP in any group of hearts (results not shown).
The results of chemiluminescence studies (PMN stimulated with FMLP) are shown in Figure 2. For each preparation of PMN, the control value (no anesthetic) was taken as 100%. The tested anesthetic drugs and Intralipid fell into two groups: those that suppressed (or at least did not elevate) the oxidative burst reaction of PMN (Fig. 2A), and those that enhanced the response (Fig. 2B).
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Thiopental showed a concentration-dependent suppression of chemiluminescence (62.3% ± 8.3% and 28.8% ± 6.2% at 50 and 500 µM, respectively, P < 0.05 versus control). Ketamine and midazolam at both concentrations tested had no significant effect on the oxidative burst.
Etomidate emulsion and Intralipid both exhibited a dose-dependent stimulation of the burst reaction. Propofol emulsion gave inconsistent results, sometimes stimulating and sometimes inhibiting the oxidative burst response: range 66%–154% at 25 µM, and range 45%–469% at 250 µM (Fig. 2B). However, when concentration-response dependencies were evaluated, propofol 250 µM induced more chemiluminescence than 25 µM propofol. Likewise, 0.44 mg/mL Intralipid induced more reaction than the smaller concentration. Interestingly, burst activity in the presence of 25 µM propofol, which contains 0.44 mg/mL Intralipid, was significantly lower than with this amount of Intralipid alone. The putative suppressing effect of propofol was no longer evident when 10 times higher levels of both constituents were compared (Fig. 2B).
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Discussion |
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In accordance with previous studies using the isolated perfused heart model, normothermic global ischemia significantly increased the adhesion of human neutrophils to the intact coronary endothelium (2–5). This has been shown to impair cardiac pump function (2–4) and to cause coronary microvascular leakage (5,6). Kowalski et al. (7) and Heindl et al. (8) have demonstrated, respectively, that volatile anesthetics reduce postischemic coronary adhesion of PMN in such heart preparations and prevent functional damage. We now show that this beneficial action is shared by some, but not all, of six common IV anesthetics. Whereas ketamine, thiopental, and midazolam blocked the postischemic increase in PMN adhesion fully when administered in clinically relevant concentrations before ischemia and during reperfusion, etomidate and fentanyl did not exert this effect. The action of propofol was indeterminate, characterized by great variability from experiment to experiment and with a tendency to enhance basal (nonischemic) adhesion of PMN.
This varied and nonuniform behavior of the IV anesthetics is not readily understandable. We have addressed several possible explanations. For instance, postischemic coronary perfusion pressure and, thus, arterial shear stress, was influenced to a certain extent by some of the tested drugs, but we were unable to detect correlations between CPP and adhesion for individual hearts in all but one group. However, postischemic intracoronary adhesion of PMN occurs mainly in the postcapillary venules (8). Thus, the present experimental model using constant coronary flow may mask detection of differences between drugs possibly evolving at much higher or lower flow rates than the ambient one used here. Unexpectedly (23), the severity of ischemic stress, as reflected by postischemic myocardial lactate production, was similar in all cases. Miller et al. (24) found that ketamine and thiopental reduced neutrophil adhesion to the rat mesenteric venular endothelium at two hours after application of tumor necrosis factor-
, suggesting a suppression of the cytokine-induced induction of E selectin expression. However, in our acute model (adhesion minutes after reperfusion), there was insufficient time for upregulation by de novo synthesis, indicating that an influence on other adhesion molecules (ß2-integrins, intercellular adhesion molecules, P selectin) is more likely.
The adhesion process is known to be enhanced by oxidative stress, such as occurs during early reperfusion, and adhesion, in turn, stimulates the oxidative burst reaction of PMN, i.e., an autocatalytic cycle exists (25,26). Direct and indirect antioxidative properties of the tested drugs could, thus, mitigate adhesion. With respect to the oxidative burst reaction of PMN, as assessed by luminol-enhanced chemiluminescence after stimulation of PMN by the chemotactic peptide FMLP, only thiopental exerted a strong antioxidative action. This result is complementary to the chemical structure of the compound, which contains a readily oxidizeable sulfhydryl group on an unsaturated heterocyclic ring. Thiopental is known to suppress the burst reaction (12), to inhibit production of superoxide anion and hydrogen peroxide (13), and to prevent neutrophil polarization (14). In agreement with previous studies, our findings suggest that the antioxidative properties of thiopental may be relevant, as free radicals and hydrogen peroxide are also assumed to enhance neutrophil adherence to the venular endothelium during early reperfusion (3,25,26). Interestingly, thiopental also reduced the basal adhesion of PMN, i.e., adhesion under conditions without ischemia and, consequently, with relatively low oxidative stress in the myocardial tissue.
In contrast to thiopental, ketamine, and midazolam (the latter two being without effect), both etomidate and Intralipid, the vehicle of propofol, gave rise to an enhancement of the oxidative burst reaction. Propofol at a high concentration (250 µM) also tended to do so, a behavior that was absent at 25 µM. In fact, chemiluminescence at 25 µM was unchanged versus control and significantly lower than with vehicle alone. This suggests that the substance propofol may, by itself, suppress the oxidative burst reaction of PMN. Stimulation of chemiluminescence by etomidate has been reported previously (27), and several studies have found propofol to cause burst suppression (28), to inhibit neutrophil polarization (29), and to act beneficially against hydrogen peroxide-induced heart injury (11).
The fact that both propofol and etomidate are pharmaceutically prepared as emulsions with soybean oil (e.g., Intralipid) is significant in this context. According to our results, the vehicle Intralipid proved to be far from inert. For instance, preischemic coronary perfusion pressure was elevated (vasoconstriction), postischemic lactate release was increased (aggravation of ischemic stress), and most pertinently, the reaction of PMN to stimulation by FMLP was enhanced. However, the ability of Intralipid to stimulate PMN varied from donor to donor—a common phenomenon when evaluating these blood cells (2–4). This variable stimulatory response to Intralipid quite likely accounts for both the general enhancement and the wide scatter of results for chemiluminescence generated in the presence of etomidate and propofol. In addition, the failure of the emulsions of etomidate and propofol to inhibit postischemic adhesion of PMN, especially when applied at larger concentrations (Fig. 1B), may be ascribed to the confounding action of Intralipid, acting as a leukocyte activator. Fittingly, Cope et al. (10) reported that propofol had no protective effect against myocardial infarction after an ischemia-reperfusion insult in rabbit hearts.
Although an explanation for the drug effect on postischemic adherence based on the antioxidative character seems likely for thiopental, the adhesion-inhibiting actions of ketamine and midazolam remain unresolved. Midazolam reportedly has some "antioxidant" properties, however, the effects on chemiluminescence and suppression of superoxide formation were observed only for concentrations far beyond the range of normal clinical plasma levels (28). As previously discussed for the case of ketamine, receptor-mediated effects may be involved (5). The failure of fentanyl to alleviate adhesion would seem to exclude a participation of µ-opioid receptors. Nevertheless, use of suitable antagonists, such as flumazenil in the case of midazolam, may help to disclose the mechanism(s) leading to inhibition of postischemic PMN adhesion by some anesthetics.
This study represents preliminary information, and other studies are needed to define the potential clinical implication. During anesthesia administration, many other drugs are given simultaneously, and these could counteract or augment the effects of individual IV anesthetics. Furthermore, the role of other blood components (platelets, monocytes, plasma proteins) has not been investigated in our model. In addition, we used a nonworking heart model and did not measure cardiac performance or transudate formation as potential markers of myocardial and vascular integrity (3,6). Although previous work has demonstrated beneficial effects of volatile anesthetics and ketamine on these variables in postischemic situations involving PMN (5,8), such experiments need to be performed for the six drugs of the present study. The fact that different anesthetics influenced PMN adherence to greatly varying extents in an intact vascular system does have an important implication for the results of studies using in vivo animal models to investigate reperfusion, preconditioning and inflammatory phenomena.
In summary, ketamine, thiopental, and midazolam, but not etomidate and fentanyl, reduce postischemic adhesion of human PMN in the coronary system and, thus, may mitigate reperfusion injury of the heart. In the case of propofol, the lipid solvent may confound the issue.
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Footnotes |
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AS is the recipient of the Research Scholarship of the European Academy of Anaesthesiology.
Presented in part at the 48th Annual Meeting of the American Society of Anesthesiologists, San Diego, CA, October, 1997.
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References |
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