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Ann Thorac Surg 2000;70:2075-2081
© 2000 The Society of Thoracic Surgeons
a Department of Cardiovascular Surgery, Center for Experimental Surgery (CREDEC), and Department of Anesthesiology, Laboratory of Thrombosis Hemostasis, University Hospital of Liège, Liège, Belgium
Accepted for publication April 27, 2000.
Address reprint requests to Dr Defraigne, CHU Liège, Domaine Universitaire du Sart-Tilman, 4000 Liège, Belgium
e-mail: jo.defraigne{at}chu.ulg.ac.be
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Abstract |
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 Top Abstract IntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
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Methods. One hundred patients undergoing coronary grafting were randomized in two groups: control group (n = 50) and test group (n = 50, surface modifying additives circuit, SMA group). Blood samples were taken before, during, and after CPB. Postoperative blood loss, number of transfused blood products, and postoperative variables were recorded.
Results. The platelet count decreased less in the SMA group compared to the control group (end of CPB: respectively, 165 ± 9 x 103/mm3 vs 137 ± 8 x 103/mm3; p < 0.01). This was paralleled by a reduction in ß-thromboglobulin plasma levels in the SMA group. There was a trend to decreased blood loss in the SMA group, but the difference was significant only in patients taking aspirin preoperatively (p < 0.05). In the SMA group nearly 50% less fresh frozen plasma and platelet units were administered (p < 0.01). No operative deaths were observed.
Conclusions. The use of circuits with surface additives is clinically safe, preserves platelet levels, and attenuates platelet activation. This may lead to a reduced need for blood products.
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Introduction |
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TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
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To spare blood or platelets, a variety of new biomaterials have been introduced, to minimize the systemic effects of blood contact with artificial surfaces. Recently, SMA circuits (surface modifying additives circuits) have become available for clinical use. During manufacture of the circuits, two copolymers (polycaprolactone and polydimethylsiloxilane) are added to the resin polymer structure [2]. During processing, these two amphipathic copolymers migrate and concentrate at the lumen surface, thus determining a mosaic structure with alternating hydrophilic and hydrophobic groups. This reduces fibrinogen adsorption and consequently platelet activation [3]. This procedure is not a coating or surface treatment that can be dislodged from the surface, because, if the modified surface is abraded, it tends to heal by "repopulation" of the abraded areas by SMA. In vitro and in vivo studies, performed in animals or in small samples of patients, have brought promising evidence that detrimental effects of the blood–biomaterial interaction may be minimized [4, 5].
The purpose of this double-blind prospective and randomized study was to examine the effects of SMA circuits on platelet count, platelet factor release (ß-thromboglobulin [ß-TG]), postoperative chest drainage volume, and perioperative blood products administration, and also on clinical results in patients undergoing CPB.
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Patients and methods |
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TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
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The patients were randomly allocated to two experimental groups of 50 patients each: standard untreated circuit (control group) and test circuit (COBE SMARxT Biocompatible Extracorporeal Circuit, COBE Laboratories, Gloucester, England) (SMA group). The perfusionist performed the assignment immediately preoperatively, by opening a sealed, numbered envelope before setup of the extracorporeal circuit. The randomization was accomplished using a random number table ("CRC Standard Mathematical Tables", 17th edition, The Chemical Rubber Company, Cleveland, OH, 1969, pp 625–629). The cannulas, tubing, and oxygenator used in these two circuits were identical in appearance, so that all members of the surgical, anesthesia, and intensive care teams, excluding the perfusionist, were blinded to the patient designation. The same two surgeons operated on each patient.
Anesthesia
Induction was performed with etomidate (0.2 mg/kg, Hypnomidate, Janssen Phamaceutica, Beerse, Belgium), sufentanyl (0.5 g/kg, Sufenta, Janssen Phamaceutica, Beerse, Belgium), midazolam (0.1 mg/kg, Dormicum, Hoffmann-La Roche, Grenzach, Germany), and pancuronium (0.1 mg/kg, Pavulon, Organon, Belgium). Anesthesia was maintained with sufentanyl (3 to 4 g · kg-1 · h-1), midazolam (0.2 mg/kg), and pancuronium (if necessary). Cefuroxime (1.5 g, Cefacidal, Bristol-Myers-Squibb, Sermoneta, Italy) was given intravenously before sternotomy as prophylaxis against infection. After endotracheal intubation, patients were ventilated to normocapnia using a mixture of oxygen and air. Before connection of the CPB circuit, heparin (300 IU/kg, Heparin Leo, Leo Pharmaceutical Products BV, Weesp, The Netherlands) was administered to achieve an activated coagulation time (Hemochron 400, International Technidyne Corp, Edison, NJ) greater than 400 seconds.
CPB
The extracorporeal circuit (COBE Laboratories, Gloucester, England) consisted of a closed venous reservoir (VRB 1200), a roller pump, a flat sheet polypropylene 1.3 m2 membrane-plaque oxygenator (CML Duo COBE), a prebypass filter (Pall, Gloucester, England), an arterial filter (Sentry, COBE), a closed cardiotomy reservoir (VRB 1800, COBE), and polyvinyl tubing. In the SMA group, all surfaces, including the cannulas and the filters, were prepared with the SMA copolymer. The standard priming of the extracorporeal circuit was 2,000 mL of gelatin (Gelofusin, Braun Medical, Emmenbrück, Switzerland) or blood depending on the expected hematocrit, with addition of 5,000 IU of heparin sodium and 100 to 150 mL mannitol 20%. The standard perfusion protocol aimed at a hematocrit of 18% to 20% during CPB.
Moderate systemic hypothermia (32°) or normothermia in some cases was used. Nonpulsatile extracorporeal circulation was initiated at a target flow rate of 2.4 L · m-2 · min-1. Venous and arterial gas were monitored (SatCrit, COBE, on the venous side and CDI 400, 3 M, Health Care, Minneapolis, MN, on the arterial side). The flow was not corrected according to temperature, but the index was sometimes increased to maintain the arterial pO2 at 160 to 180 mm Hg and the pCO2 at 40 mm Hg. Base excess was not corrected until pH 7.2. After aortic cross-clamping, a single dose of approximately 800 mL (600 to 1000 mL) of cold (4°C) high-potassium crystalloid cardioplegia (St Thomas Hospital No. 1 cardioplegic solution) was infused into the aortic root to provide myocardial preservation. Topic pericardial cooling was used during the infusion of the cardioplegic solution. During CPB, additional heparin was administered if the activated coagulation time was lower than 400 seconds. Extracorporeal circulation was terminated at an esophageal temperature of 35°C. After CPB was completed, heparin was neutralized with protamine sulfate (1 mg per 100 IU heparin). During the CPB, no pump suction was used and all shed blood was retrieved with a cell-saving device. After termination of the CPB, the residual volume in the perfusion circuit was collected in the cell-saving device, washed, and returned to the patient.
Blood samples
Venous blood samples for estimation of hematocrit, platelet count, and ß-TG release were drawn on eight occasions: before the induction of anesthesia (T1), before surgery (T2), after heparin administration (T3), after the start of CPB and before aortic cross-clamping (T4), after aorta unclamping (T5), at the end of CPB (T6), 1 hour after surgery (T7), and 24 hours after surgery (T8). On each sample, the platelet count and hematocrit were determined automatically (Technicon H2, Bayer, Leverkusen, Germany).
ß-Thromboglobulin (ß-TG) assay technique
Blood was collected in sterile evacuation blood collection tubes containing ethylenediaminetetraacetic acid. The tubes were immediately placed in an ice-water bath for 15 minutes. They were then centrifuged at 2° to 8°C (2,500 g for 30 minutes). The upper part of the plasma supernatant was recovered, immediately frozen, and stored at -70°C until analysis. The ß-TG concentration was determined with enzyme immunoassay sandwich procedures using a commercially available kit (Asserachrom ß-TG, Diagnostica Stago, Asnières, France). Results were corrected for hemodilution at each time point.
Clinical data
Postoperative chest drainage volume, incidence of blood products administration, operative mortality (within 30 days), and incidences of complications were analyzed. Packed red blood cells were administered if the hemoglobin level was lower than 8 g/dL, or higher than 8 g/dL in the presence of associated conditions (age > 70 years, systolic blood pressure < 90 mm Hg, heart rate > 100 beats/min, cardiac index < 2.2 L · min-1 · m-2). Platelets were administered when the platelet count was lower than 70,000/mm3 or when excessive bleeding was observed despite desmopressin or fresh frozen plasma administration.
Data analysis and statistics
The results were expressed as mean ± standard error of the mean (SEM). The Student’s t test and the F test for paired and unpaired samples were used for statistical analysis of differences between control values and different time points within one group, or differences between the two groups at the same time points. Data that was not normally distributed were analyzed using the Mann–Whitney or Wilcoxon tests. Categorical variables were analyzed using a 
2 test. A p value of less than 0.05 was considered to indicate a statistically significant difference between measured values.
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Results |
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TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
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Hematocrit
The variations of the hematocrit are depicted in Figure 1. In both groups, the hematocrit value significantly decreased from the start of CPB and remained significantly decreased 24 hours after surgery. No significant intergroup differences were observed.
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Mortality and morbidity
No postoperative deaths were observed.
The incidences of complications for the two groups were not significantly different. Four patients required resternotomy: 2 for bleeding (bleeding exceeding 10 mL/kg in the first postoperative hour or an average of 5 mL/kg in the first 3 postoperative hours) in the control group, and 1 for bleeding and 1 for cardiac failure in the SMA group. One patient in each group presented with postoperative myocardial infarction (2% of incidence). Eight patients in the control group and 9 in the SMA group developed postoperative atrial fibrillation. Four patients had transient elevation of the serum creatinine, 2 of them (1 in each group) requiring temporary ultrafiltration. Postoperative neurologic disturbances manifested as encephalopathy were observed in 6 patients (3 in the control group and 3 in the SMA group). Six patients (3 in each group, 6%) needed prolonged respiratory assistance beyond 24 hours. Intensive care stay (2.8 ± 0.3 days in the SMA group vs 2.70 ± 0.2 days in the control group) and hospital stay (11.8 ± 0.6 days in the SMA group and 11.3 ± 0.7 days in the control group) were not significantly different.
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Comment |
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TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
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Aside from a decrease in the platelet count, progressive loss of platelet function is observed within minutes after starting CPB [6–9] and worsens throughout CPB, as demonstrated by impairment of platelet aggregation to adenosine diphosphate or collagen. Although not easily performed during CPB, the bleeding time measurement is a sensitive method for assessment of platelet dysfunction. An increase in bleeding time early after starting CPB appears independent of the modest reduction in the platelet count, with a normalization by to 2 to 4 hours after the end of the CPB. Although several mechanisms have been proposed for platelet dysfunction, it is probably a consequence of transient platelet activation, similar to the "refractory state" induced in vitro by adenosine diphosphate [10, 11]. Simultaneously to this activation, several markers of platelet activation such as platelet factor 4 and ß-TG are released in the plasma and urine [6, 12]. Elevated plasma levels of ß-TG, which makes up 10% of the contents of 
-granules, occur during platelet activation consecutive to various agonists or circumstances, and progressive increases in plasma and urine levels of platelet factor 4 and ß-TG have been reported during CPB [1, 6, 9, 13]. In an in vitro simulated CPB circuit, Colman [14] showed that platelets secrete the contents of the -granules as reflected by an increase in the plasma levels of ß-TG. In association to this, platelets appeared degranulated on electron microscopy.
Several pharmacologic strategies have been proposed to prevent or reduce platelet dysfunction during CPB either prophylactically or in case of severe bleeding, such as infusion into the bypass circuit of prostaglandins [15] or prostacyclin [16], treatment with low or high doses of aprotinin [17, 18], or desmopressin infusion [19]. Nevertheless, aside from the cost increase, another potential drawback of such therapies is an increased rate of myocardial infarction [17]. Both biomaterial independent and biomaterial dependent factors contribute to platelet activation after CPB. Mechanical trauma forces (shear stresses, turbulences), blood contact with foreign surfaces, blood–air interfaces, pericardial and pleural stagnation of blood, surgical manipulation, and hypothermia are all contributive mechanisms to blood activation and platelet dysfunction and consumption [20]. Thus, efforts to improve biocompatibility and reduce platelet activation should be directed toward the design and geometry of the circuit, but also to modification of the physicochemical nature of the surface in contact with blood. Heparin-coated circuits have been evaluated in this perspective but results were mitigated [20, 21].
The purpose of our study was to evaluate the impact of a novel biomaterial in terms of platelet consumption, platelet factor release, postoperative blood loss, and need for transfusion. In this material, SMA were incorporated into the base polymer. During the manufacturing process, these additives migrate to the lumen surface yielding a stable microdomain-like configuration, which reduces the interfacial energy and surface tension while preserving the basic bonds with the bulk material [3]. A modified perfusion technique was also used because the circuit was a closed one in which blood–air contact was minimized.
In the present trial, because of hemodilution, the platelet count rapidly and significantly decreased in both experimental groups soon after starting CPB, as observed by several authors [1, 6–8]. This decrease was not solely related to hemodilution because after correction for the hematocrit variations, the platelet count remained significantly decreased at the end of CPB and at 1 and 24 hours after CPB, which is parallel to the results of van Oeveren and colleagues. Nevertheless, compared to the control group, the platelet count in the SMA patients was significantly higher at the end of CPB and 1 hour after CPB. Twenty-four hours after CPB, no significant difference was observed between the two groups, although the platelet level tended to be higher in the SMA group. It should, however, be underlined that the number of platelet units transfused in the control group was nearly double when compared to the SMA group. One may thus anticipate that the differences would have been significant after 24 hours if the same number of platelet units had been transfused in the two groups, because the platelet count usually requires several days to spontaneously correct.
ß-Thromboglobulin levels were within normal range before induction. They increased significantly in both groups after heparin administration and rose continuously from the start until the end of CPB, peaking at the end of CPB. Complete normalization of plasma platelet factor 4 and ß-TG levels usually occurs within the first 2 to 4 postoperative hours, and in our study ß-TG levels returned toward baseline levels after 24 hours. The pattern of ß-TG release that we observed is similar to those reported by several teams [1, 13, 16]. However, the levels at the end of CPB and 1 hour after CPB were significantly lower in the SMA group than in the control group, therefore reflecting less activation in the test group. It is striking that it is precisely at these time points that the platelet count was significantly higher in the SMA group. This result reflects less platelet activation in the SMA group. For example, Aren and coworkers [16] have shown that prevention of platelet activation with prostacyclin drastically reduces plasma levels of ß-TG.
The SMA were designed originally for the manufacture of the blood sac of Thoractec’s ventricular assist device. Animal and human studies performed with this material during long-term ventricular assistance showed a reduction of platelet consumption with preservation of the platelet count and a decrease in the incidence of thromboembolic complications [22]. The SMA minimize the denaturating of adsorbent plasma proteins and reduce fibrinogen adsorption at the lumen surface of the circuit. As fibrinogen binding to platelets through GPIIa–III receptors is the biochemical correlate of platelet aggregation [9, 11], this perhaps explains the protective effect of SMA on platelet count and the decreased plasma levels of ß-TG. In this perspective, in a pilot clinical study performed with a small number of patients, Rubens and colleagues [23] recently demonstrated that the use of SMA circuits produced less platelet activation as reflected by decreased expression of platelet-GMP 140, parallel to decreased thrombin generation and release of tissue plasminogen activator. In contrast, Gu and coworkers [5] did not show any difference in ß-TG plasma levels between standard and SMA circuits. However, platelet deposition on the CPB circuit was significantly less in the SMA group than in the control group as assessed by a labeled monoclonal antibody against platelet glycoprotein IIIa, and these authors concluded that SMA inhibited platelet interaction with the surface of the circuit. The discrepancy with our results may perhaps arise from the small number of patients included in that study (10 in each group) compared to the larger number of patients included in the present report (50 in each group). Because of individual responses, larger clinical studies are in fact needed [20, 21], and this was the purpose of the present report. In another field, Jessen and colleagues [4] demonstrated in a porcine model of CPB that treatment with SMA significantly decreased polymorphonuclear leukocyte deposition in the oxygenator. This may also reflect improved biocompatibility, although Gu and colleagues [5] found no difference in terms of leukocyte activation.
Aside from release from degranulating platelets, increases in plasma ß-TG or platelet factor 4 may also originate [6, 8, 9, 11] from platelet lysis in vivo or in vitro or from artifactual in vitro degranulation and secretion as a result of separation of plasma from platelets before the performance of the assays. Platelets are in fact very sensitive to stimuli, and sampling for ß-TG measurement requires caution, such as collection of blood on ice and cooling during centrifugation. In the present report, the assay method for ß-TG was identical for both groups, thus excluding that as a potential bias in the observed differences. The baseline and peak levels in our control group are lower than those reported by some authors. This is probably because of the type of oxygenator used in some studies (bubble oxygenator) [1, 16], but also could be because of the technical characteristics of the assay [1]. In our study, the use of a closed venous reservoir minimizing blood–air contact and avoidance of pump suction of the shed blood may also have contributed to lower plasma levels of platelet activation marker, because it has been shown that return of the shed blood to the patient may contribute to various blood activations.
Differences in blood loss might be from surgical technique. To reduce such a bias, all patients were operated on by the same two surgeons. The technique used for surgical hemostasis and the time spent on hemostasis were strictly standardized. Postoperative chest drainage tended to be lower in patients operated on with the SMA circuit, although the difference did not reach statistical significance if the entire series of patients was considered. Patients in the control group received more platelet and fresh frozen plasma units, which may have influenced the amount of blood loss. It is not unwise to suggest that if the amount of platelet or plasma administration had been the same in both groups, differences in blood loss could be more marked. In fact, although prophylactic platelet transfusion is not indicated in these patients [6, 24], it is obviously indicated in patients with excessive bleeding who are receiving blood replacement after CPB. Patients taking aspirin before coronary artery bypass grafting have excessive and prolonged mediastinal bleeding, complicating CPB [25]. Interestingly, if the patients who received aspirin preoperatively were considered apart, the difference in blood loss was significant. The magnitude of blood loss reported here is of the same order as that reported in previous studies in patients taking aspirin and being treated with aprotinin. For example, in the study by Murkin and colleagues [25], the mean total blood loss in aspirin-treated patients reached 1,409 mL with aprotinin and 2,765 mL without aprotinin, 59% and 88% of the patients, respectively, being transfused with and without aprotinin.
The amount of blood product administration appears to be a more significant factor than estimation of blood loss alone. In fact, in the present study, the amount of blood loss was higher than we usually observe in our patients receiving routine aprotinin. No aprotinin was used here, which explains the higher blood loss. No difference between the two groups was observed for packed red blood cells, despite the fact that there was a higher proportion of female patients in the SMA group with a lower preoperative hematoctit value (data not shown). Nevertheless, the fact that patients in the control group received two times the number of platelet or fresh frozen plasma units highlights the benefit of using the SMA circuit.
Finally, from a clinical point of view, no operative deaths occurred in either group. The rate of complications was similar in both groups, and the length of intensive care and hospital stays were similar in both groups, thus demonstrating that coating with SMA is safe.
In conclusion, in our trial, the use of circuits with surface additives preserved the platelet levels. This effect is associated with a decrease in plasma levels of platelet factor (ß -TG), reflecting less platelet activation. The main benefit of SMA circuits resides in the reduction of blood product transfusions, which may reduce the costs of surgical procedures and limit the risks of transmitted diseases, such as hepatitis and AIDS. The clinical results demonstrate the safety of using SMA circuits. In the future, the benefits of SMA circuits must be explored in addition to other platelet-sparing strategies such as aprotinin administration.
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Acknowledgments |
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TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
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References |
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TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsReferences |
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-granule release. Blood 1980;56:824-830.2-adrenergic receptors during simulated extracorporeal circulation:prevention with prostaglandin. J Lab Clin Med 1985;105:601-605.[Medline]
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