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CARDIOVASCULAR ANESTHESIA

Platelet Function and Anesthetics in Cardiac Surgery: An In Vitro and Ex Vivo Study

Alessandro Parolari, MD, PhD^*, Daniela Guarnieri, BS, Francesco Alamanni, MD^*, Thomas Toscano, MD, PhD^*, Vito Tantalo, MD, Tiziano Gherli, MD, Susanna Colli, PhD^§, Fabrizio Foieni, MD^||, Vincenzo Franzè, MD^*, Monica Stanghellini, CCP^*, Gian Angelo Gianotti, MD, Paolo Biglioli, MD^*, and Elena Tremoli, PhD^§

*Department of Cardiac Surgery, University of Milan, Milano; Transfusional Center, Istituti Clinci di Perfezionamento, Milano; Department of Cardiac Surgery, University of Parma, Parma; §Institute of Pharmocological Sciences, University of Milan, Milano; and ||Clinical Pathology Laboratory, Centro Cardiologico IRCCS, Milano, Italy

Address correspondence and reprint requests to Alessandro Parolari, MD, Department of Cardiac Surgery, University of Milan, Centro Cardiologico, Fondazione I Monzino IRCCS, Via Parea, 4, 20138, Milano, Italy. Address e-mail to corallo{at}imiucca.csi.unimi.it

	Abstract

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We studied the effects of the anesthetics commonly used in cardiac surgery on platelet function. Fentanyl, droperidol, succinylcholine, pancuronium, thiopental, and diazepam at therapeutic concentrations were tested for their in vitro effects on the expression of platelet membrane glycoproteins Ib and IIbIIIa (GpIb, GpIIb-IIIa) and of P-selectin in anticoagulated whole blood by flow cytometry. The expression of P-selectin was determined under basal conditions, after the incubation of blood with adenosine diphosphate (ADP) 10 µmol/L, and the stable prostaglandin endoperoxide analog U46619 1 µmol/L. No drug affected the expression of P-selectin in unstimulated and ADP- or U46619-stimulated platelets, with the exception of thiopental, which markedly decreased the U46619-induced expression of P-selectin. Thiopental concentration-dependently inhibited U46619-induced and ADP-induced platelet aggregation, with effects on U46619-induced aggregation at therapeutic concentrations. To assess ex vivo effects, the same platelet markers were also assessed in blood obtained from 10 patients undergoing elective coronary surgery. Compared with basal values, platelet response to U46619 was significantly reduced just after the administration of anesthetic drugs, and the effect persisted for 48 h after surgery. Our study suggests that, at therapeutic concentrations, thiopental inhibits U46619-induced platelet activation both in vitro and ex vivo. The mechanisms responsible of this effect, together with its clinical significance, require further investigation.

Implications: Thiopental inhibited prostaglandin-induced platelet activation at therapeutic concentrations both in vitro and ex vivo in cardiac surgical patients whereas adenosine diphosphate-induced activation was affected only at supratherapeutic drug concentrations. Thus, administration of sodium thiopental may contribute to the in vivo impairment of platelet function in patients undergoing elective cardiac surgery.

	Introduction

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Excessive bleeding associated with cardiopulmonary bypass (CPB) is still a major concern in cardiac surgery, and alterations of hemostasis have been extensively described during cardiac surgical procedures. Transient platelet dysfunction is believed to be one of the main determinants of postoperative bleeding (1). Platelet aggregation is affected by some of the drugs commonly used to induce and maintain general anesthesia, but the mechanisms responsible for this phenomenon remain unknown (2–9).

Recent advances in flow cytometry have allowed the detection of platelet activation in whole blood, both in the basal condition and after stimulation with agonists (10,11). Using this technique, we assessed the effects of the anesthetic drugs commonly used in cardiac surgery on platelet function in vitro and ex vivo in blood of patients undergoing CPB. The platelet surface expression of P-selectin, which is expressed on the platelet membrane surface only after activation, and of the glycoproteins Ib (GP Ib) and IIb-IIIa (GP IIbIIIa), an index of membrane integrity, was measured. Platelet function was assessed both in the basal condition and after exposure to a weak platelet agonist, adenosine diphosphate (ADP) or a strong agonist (U46619, a stable analog of thromboxane A2), which may be considered indexes of platelet hemostatic capacity.

	Methods

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In Vitro Study
Platelet activation was studied in blood from 10 normal volunteers who did not receive any drugs influencing platelet function for at least 10 days. The methods and the techniques were previously described by Shattil et al. (11).

Whole blood samples (2.5 mL) were carefully withdrawn without stasis from a peripheral vein through a 19-gauge needle in plastic tubes containing 0.25 mL of sodium citrate 3.8% (9:1 vol/vol); blood samples were processed within 3 min. Six 5-mL aliquots of whole blood were put into plastic tubes containing 45 mL of phosphate-buffered saline and 1% bovine serum albumin. A saturating concentration of anti–P-selectin monoclonal antibody (10 mL) (CD62; Becton Dickinson, Mountain View, CA) was added to four of the six tubes; after 15-min incubation at room temperature without stirring, 20 mL of fluorescein isothiocyanate was added to the four tubes. One tube was used to evaluate cellular autofluorescence, and the second to evaluate platelet activation under basal conditions, while the remaining two were used to evaluate platelet response to ADP (10 µmol/L) or to a stable analog of thromboxane A2 (U46619; 1 µmol/L). The last two tubes were incubated with 10 µL of a saturating concentration of a monoclonal antibody anti-GpIb or anti-GpIIb-IIIa (Immunotech, Marseille, France), which allowed evaluation of the surface platelet expression of the von Willebrand factor receptor GPIb and of the fibrinogen receptor GPIIb-IIIa, respectively. After incubation for another 15 min at room temperature, 500 mL of 1% paraformaldehyde solution was added to all tubes to stop platelet activation. All samples were then analyzed by a flow cytometer (FACSscan; Becton Dickinson, Mountain View, CA), which distinguishes platelets from erythrocytes and white blood cells based on their forward- and side-light scatter profile. A gate was set around the platelets, and 5000 cells were analyzed for fluorescein isothiocyanate fluorescence to quantify the amount of platelet-bound anti–P-selectin, anti-GpIb, or anti-GpIIbIIIa antibodies. Antibody binding was expressed as the percentage of platelets positive for the antibody, after subtraction of cell autofluorescence.

The reproducibility of the assay was assessed on blood obtained from eight normal volunteers: four were tested three times on the same day, and four were tested once on 3 consecutive days. There were no differences between the two subgroups, and the mean coefficients of variation were 0.3% for basal P-selectin measurements, 3.9% after the addition of ADP, and 5.4% after the addition of U46619.

Anesthetics were incubated for 15 min with whole blood at the following therapeutic concentrations: fentanyl (1 ng/mL), droperidol (1 ng/mL) succinylcholine (25 mg/mL), pancuronium bromide (80 ng/mL), thiopental (10 µg/mL), and diazepam (500 ng/mL).

Ex Vivo Study
The effect of the anesthetics on platelet function was also studied in patients undergoing coronary artery surgery. Platelet function was assessed in two different subsets of 10 patients. The first 10 patients were studied 10 min before and 10 min after the administration of the anesthetics, when no drug administration was allowed except for crystalloid solutions to maintain an adequate blood pressure (pilot study). A time course study of platelet activation was then performed on 10 different patients, and blood samples were collected at seven different times: the day before surgery (baseline) and on entering the operating room, before arterial and venous catheter insertion, and before anesthesia induction (baseline 2); 10 min after the induction of anesthesia and the administration of anesthetics, and before the aprotinin bolus (anesth); at the end of the 30-min aprotinin bolus (aprotinin); 60 min after the beginning of CPB (CPB60); 10 min after protamine administration (protamine); 24 h after surgery (24h); and 48 h after surgery (48h).

The protocol was approved by the Ethical Committee of the Centro Cardiologico IRCCS, and written, informed consent was obtained from all patients. All the cases were managed by the same cardiac surgical and anesthesia team. In all cases, the preoperative ejection fraction was >30%, and the left ventricular end-diastolic pressure was <20 mm Hg. Exclusion criteria were age >75 yr, renal or liver disease, intake of drugs affecting platelet function, or coagulation or fibrinolysis within 10 days before surgery. The clinical features of the study population are reported in Table 1; all the patients had an uneventful postoperative course, and no patient required reexploration for bleeding or intraoperative donor blood transfusion.

Intraoperative Management
Management of patients during and after surgery was substantially the same. All patients received standard moderate-dose fentanyl and benzodiazepine anesthesia, which was induced by the administration of the following substances: thiopental (3 mg/kg), fentanyl (0.75 µg/kg), succinylcholine (1 mg/kg), diazepam (10 mg), and pancuronium bromide (0.1 mg/kg).

After the induction of anesthesia, patients were ventilated with intermittent positive pressure ventilation and supplemental oxygen. Fentanyl (with or without droperidol), diazepam, and pancuronium bromide were administered in bolus doses when necessary. Aprotinin (Trasylol; Bayer, Leverkusen, Germany) was given according to the high-dose protocol (12). After median sternotomy, bovine lung heparin (Liquemin, Roche, Italy) was administered (300 IU/kg) directly in the right atrial appendage before cannulation of the heart. The test for celite-activated clotting time (ACT) was performed before the start of CPB, then at 20-min intervals. Another heparin dose (100 IU/kg) was given when ACT was <800 s (13).

Hollow-fiber oxygenators (Capiox SX; Terumo, Rome, Italy) were primed with 1.5 L of lactated Ringer's solution containing 2500 IU of heparin. No blood was added to the prime of the circuit. Polyvinyl chloride tubing was used throughout the CPB circuit, except for the pump tubing, which was made of silicone rubber. Sorin ABF 40 (Sorin Biomedica, Saluggia, Italy) 40-mm blood filters were interposed in the arterial line of the CPB circuit.

Each operation was performed with moderate systemic hypothermia (30–32°C) and hemodilution (hematocrit values 20%–24%). Blood flow during CPB was maintained at 2.4 L/m2 body surface area per minute; acid-base equilibrium was maintained by using the -stat method.

Myocardial protection was achieved by antegrade and/or retrograde infusion of 1000 mL of cold (4°C) crystalloid cardioplegic solution repeated (250 mL) every 20 min of aortic cross-clamp time.

Continuous variables are expressed as mean ± SD; categorical variables are expressed as percentages. All data were analyzed with a commercial computer statistical software (SPSS for Windows, ver. 6.0; SPSS Inc., Chicago, IL). Statistical analysis was performed by using the Student's t-test for paired or unpaired samples when indicated. For the ex vivo study, a general linear model repeated-measures analysis of variance procedure was used to explore data for sequential measurements; when a significant (P < 0.05) F ratio was detected, multiple comparisons within groups between baseline and other measures were made with univariate analysis of variance with Duncan's correction. Statistical significance was set at P < 0.05.

	Results

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In Vitro Study
In the unstimulated condition, the different anesthetics did not significantly influence the expression of P-selectin on platelet surface. The drugs tested did not affect the percentage of ADP-stimulated P-selectin–positive platelets; similarly, no effect of the drugs was detected in regard to U46619-induced platelet activation, with the exception of thiopental, which decreased the U46619-induced expression of P-selectin from 74% ± 10.8% to 15% ± 8.7% (-80%; P < 0.01) (Fig. 1). The effect of thiopental on P-selectin expression was concentration-dependent (0.1–1000 mg/mL) with a 50% inhibitory concentration (IC₅₀) value of 94.8 ± 45.5 and 7.2 ± 6.8 mg/mL for ADP and U46619, respectively (P < 0.001) (Fig. 2). No tested drug influenced the surface expression of the GPIb and GPIIbIIIa in both baseline and stimulated conditions (data not shown).

View larger version (24K): [in this window] [in a new window]   Figure 1. Effect of the incubation of blood from 10 different healthy donors with the anesthetic drugs on the expression of P-selectin by platelets at baseline and after stimulation with 10 µM adenosine diphosphate or 1 µM U46619. Values are the means ± SD of 10 determinations for each condition performed in duplicate. *P < 0.01 versus baseline.

View larger version (21K): [in this window] [in a new window]   Figure 2. Concentration-response effect of thiopental on the expression of the platelet antigen P-selectin after stimulation with adenosine diphosphate (10 µM) or U46619 (1 µM). Concentration-response curve of the incubation of platelets from 10 different healthy donors with increasing doses of thiopenthal. Each point is the mean ± SD of 10 different observations performed in duplicate.

Platelet GpIb and GpIIbIIIa expression did not significantly change throughout the study. The percentage of GpIb-positive platelets ranged between 95% and 99%, whereas the percentage of platelets expressing surface GpIIbIIIa ranged between 97% and 99% (data not shown). These values are all within the normal range for healthy adult patients.

The percentage of P-selectin–positive platelets was very low at baseline, after anesthesia induction and aprotinin bolus administration, and during CPB (2.5% ± 2.7%), whereas it increased by threefold after protamine administration (8.0% ± 5.2%; P < 0.05). Platelet stimulation with ADP markedly increased P-selectin expression at all the times considered, ranging between 39% and 52%.

Similarly, U46619 significantly increased the expression of P-selectin by platelets compared with unstimulated cells. Interestingly, the platelet expression of P-selectin induced by U46619 decreased by 50% immediately after anesthesia induction (60% ± 9.8% and 28% ± 7.9% for baseline and after anesthesia induction, respectively; P < 0.05). The impairment in platelet P-selectin expression reached a maximum 60 min after the start of CPB (14.5% ± 6.9%; -76% compared with baseline levels; P < 0.05), remained low after protamine administration (25.2% ± 11.8%; -58%; P < 0.05), and returned to baseline 48 h after surgery (Fig. 3).

View larger version (14K): [in this window] [in a new window]   Figure 3. Time course of the expression of platelet glycoproteins GpIb and GpIIbIIIa and of the platelet antigen P-selectin under both baseline and stimulated (adenosine diphosphate 10 µM and U46619 1 µM) conditions. Values are expressed as percent changes with respect of the baseline. Each point is the mean of the 10 different observations ± SD. *P < 0.05 versus baseline.

	Discussion

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The effects of thiopental and other barbiturates on platelet function have also been studied, mainly in experimental animals. Aggregation of rat platelets in response to ADP or arachidonic acid was shown to be by affected by thiopental, but this effect was detectable only at plasma concentrations higher than those achieved during clinical anesthesia (5). Phenobarbital and other barbiturates were shown to decrease dog platelet aggregation in response to ADP (6).

Studies performed in humans on effects of the different barbiturates on platelet function are conflicting. An in vitro potentiation of human platelet aggregation by thiopental, with an increased basal and stimulated free cytosolic calcium concentration, has been described; this effect was not shared by other barbiturates such as pentobarbital and methohexital, which, instead, decreased platelet aggregation without apparently influencing calcium metabolism (8).

Cardiac surgical procedures induce profound alterations in hemostatic function, the most predictable of which is platelet dysfunction. Under these conditions an impairment of platelet function is believed to be of multifactorial origin, although the interaction between platelets and the synthetic surfaces of the CPB circuit is highly implicated in this phenomenon (9).

No previous studies assessed the relation between the in vitro and in vivo effects on platelet activation of drugs commonly used to induce and maintain general anesthesia in cardiac surgery. Platelet activation in response to ADP and U46619 was assessed by flow cytometry, which has advantages over conventional methods such as aggregometry, assays of ß-thromboglobulin, platelet factor 4, metabolites of thromboxane A₂. Using this methodology, platelet activation can be assessed in a physiologic environment (whole blood), both in the basal activation state and in response to different agonists. Very small subpopulations of activated platelets can be detected using flow cytometry (10). Moreover, the assessment of P-selectin expression represents a marker of platelet activation and -granule secretion (10,11).

Our in vitro data show that, among the anesthetic drugs commonly administered for elective cardiac surgery, only thiopental at therapeutic concentrations markedly impairs the prostaglandin-induced platelet expression of P-selectin. In addition, thiopental inhibits ADP-induced platelet P-selectin expression, but only at supratherapeutic concentrations of the drug.

Ex vivo data obtained in blood from patients undergoing CPB indicate that soon after anesthesia, before the start of surgery, a marked reduction in agonist-induced P-selectin expression can be observed, which can be likely ascribed to the administration of thiopental. The time course study showed that the impaired platelet response to prostaglandins occurring soon after anesthesia induction lasted up to 48 h after surgery, an effect longer than would be predicted from the half-life of thiopental. Two explanations for this discrepancy include the possibility of a persistent effect of thiopental on platelet activation not necessarily related to plasma drug levels and other factors, probably related to CPB, which may contribute to the persistence of this effect up to 48 h. It can be hypothesized that the inhibition of prostaglandin-induced platelet activation induced by thiopental is accompanied by a more general impairment of platelet function subsequently related to CPB.

The previously reported effects of thiopental on platelet aggregation were detected at drug concentrations higher than those used in humans (5,14). Preliminary studies performed by our group indicate that thiopental reduces the aggregation of platelet-rich plasma at concentration 10- to 100-fold greater than those active on P-selectin expression. In those experiments, thiopental showed the following potency: U46619 > collagen > ADP (data not shown). Thus, the two processes (expression of P-selectin and in vitro response to aggregating drugs) may differ in terms of sensitivity to this inhibitor.

A potential limitation of the ex vivo time course study in patients undergoing CPB is that all patients were administered the antifibrinolytic drug aprotinin intraoperatively. A control group of patients not receiving aprotinin, however, could not be included for ethical reasons, because large-dose aprotinin is routinely used at our center because it significantly reduces the need for blood transfusions in these patients, as well as the reexplorations for bleeding (13), which adversely affects the outcomes of patients undergoing cardiac surgical procedures (15). It is, however, unlikely that the impairment of platelet function could be ascribed to aprotinin administration because it was detected before its administration (after anesthesia). Some published data indicate that aprotinin does not influence platelet function or activation, being active only on CPB-related fibrinolysis (16–19).

In conclusion, our study indicates that, among several anesthetic drugs commonly used in cardiac surgery, therapeutic concentrations of thiopental inhibit in vitro prostaglandin-induced platelet expression of P-selectin, whereas it affects ADP-induced activation only at supratherapeutic concentrations. A similar pattern of inhibition of P-selectin expression was also documented ex vivo, a few minutes after the administration of thiopental but before the start of coronary artery surgery with CPB. The mechanism responsible for this inhibition and the clinical significance of this effect need further investigation.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999