Ann Thorac Surg 1996;62:506-511
© 1996 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Efficacy of Aprotinin With Various Anticoagulant Agents in Cardiopulmonary Bypass
Mark R. Terrell, MD,
Jeanine M. Walenga, PhD,
Michael J. Koza, BS,
Roque Pifarré, MD
Department of Thoracic and Cardiovascular Surgery, Loyola University Medical Center, Maywood, Illinois
Accepted for publication March 26, 1996.
 |
Abstract
|
|---|
Background. Aprotinin has recently been approved for clinical use in cardiopulmonary bypass. Although unfractionated heparin has been the only anticoagulant widely used for cardiopulmonary bypass, disadvantages involving heparin have led to ongoing investigations of alternative anticoagulant agents.
Methods. The objective of this study was to evaluate the efficacy of aprotinin in combination with other anticoagulant agents, specifically low molecular weight heparin and recombinant hirudin, using a dog model of cardiopulmonary bypass.
Results. The blood conservation resulting from the use of aprotinin was observed only with unfractionated heparin. Efficacy of anticoagulation as measured by protein deposits in the bypass circuit filter revealed an unexpected reduction in the quantity of deposits when aprotinin was used in combination with low molecular weight heparin.
Conclusions. As alternative anticoagulant agents are sought, the potential benefits of aprotinin in the reduction of operative blood loss must be evaluated independently for each anticoagulant agent.
|
Introduction
|
|---|
To date, heparin has been the mainstay of anticoagulation therapy for cardiopulmonary bypass (CPB). Although the anticoagulant effect is reversible with protamine, procedures involving CPB have been accompanied by relatively high levels of blood loss intraoperatively and postoperatively. The serine protease inhibitor aprotinin has been shown to reduce blood loss and transfusion requirements significantly after CPB [1–3]. However, the mechanism of action of aprotinin remains controversial.
Disadvantages of heparin have led to the search for safe and effective alternatives for anticoagulation during CPB. The primary objective of this study was to assess the efficacy of aprotinin when used in conjunction with anticoagulants other than unfractionated (UF) heparin, specifically low molecular weight (LMW) heparin and recombinant (r-) hirudin. Although LMW heparin has some of the disadvantages of UF heparin, LMW heparin has a longer half-life and has been shown to provide adequate anticoagulation for a 90-minute period of CPB in a canine model with a single bolus dose [4, 5]. Recombinant hirudin is a specific thrombin inhibitor that has been shown to provide predictable dose-dependent anticoagulation in our canine model of CPB, with lower levels of perioperative blood loss than are associated with UF heparin [6]. In this study, we sought to determine whether blood loss with LMW heparin and r-hirudin could be reduced further with the addition of aprotinin, without compromising the anticoagulant efficacy of each agent.
|
Material and Methods
|
|---|
Forty-nine male mongrel dogs (22 to 30 kg) were divided into six groups, encompassing three different anticoagulant agents with and without aprotinin treatment. Dogs were sedated with intramuscular Xylazine (1 mg/kg), followed by induction of anesthesia with intravenous pentobarbital (30 mg/kg). After intubation and preparation of operative sites, the dogs were ventilated with a Harvard (Harvard Apparatus, South Natick, MA) ventilator to 2.5 cm positive end-expiratory pressure. Bilateral femoral cutdowns were performed for vascular access, using both femoral veins and the right femoral artery. Median sternotomy and pericardiotomy were performed for access to the heart and the proximal ascending aorta for cannulation.
After placement of pursestring sutures in the aorta and right atrial appendage, bolus anticoagulant agents were administered by intraatrial injection, as follows: UF heparin (Institut Choay, Paris, France), 2.5 mg/kg; LMW heparin (Sandoz AG, Nürnberg, Germany), 3.0 mg/kg; and r-hirudin (Ciba Pharmaceuticals, Horsham, UK), 1.0 mg/kg followed by an intravenous infusion of 2.25 mg • kg-1 • h-1. In the groups treated with aprotinin (6,120 KIU/mg; Pentapharm, Basle, Switzerland), administration was by bypass circuit reservoir prime only (2 million KIU) or 2 million KIU by a combination of bolus intravenous injection, reservoir prime, and an infusion during the period of bypass. The total dosage of 2 million KIU is roughly equivalent on a weight-adjusted basis to the dosage clinically used in humans, although in neither situation are dosages adjusted to the weight of the individual subjects. The standard "Hammersmith" regimen has proven to be effective across a range of patient weights, as in the studies mentioned previously.
Aortic and right atrial cannulations were performed and the animals were placed on CPB, using a Travenol (Travenol Laboratories, Inc, Ann Arbor, MI) roller pump primed with lactated Ringer's solution and a sterile variable-prime Cobe (Cobe Laboratories, Inc, Lakwood, CO) membrane lung blood oxygenator with sterile Tygon (Norton Performance Plastics, Akron, OH) tubing and sterile Pall (Pall Biomedical Products, East Hills, NY) 40-µm blood filters. Cardiopulmonary bypass was maintained for a mean of 90 minutes. Blood samples were collected at 5 minutes on bypass, at 15 minutes, and every 15 minutes thereafter during the bypass period. At the end of the bypass period and immediately after decannulation, protamine was given in those dogs that received anticoagulation with UF heparin.
All blood was then suctioned from the chest, measured, and discarded. Intraoperative blood loss data were not analyzed because blood loss during the cannulation and decannulation procedures was unavoidably variable and obviously due to technical factors, and unrelated to the activities of the drugs under investigation. The arterial filter from the bypass circuit was rinsed with 1 L of normal saline and saved for later analysis. A 2-hour post-bypass observation period ensued, with blood samples collected at 5 minutes after bypass, 15 minutes after bypass, and every 15 minutes thereafter during the observation period. The animals were then sacrificed using saturated potassium chloride solution, and the chest was immediately suctioned thoroughly for removal of all free blood in the pericardial and pleural cavities. Post-bypass blood loss data were collected as volume/weight (mL/kg).
Because the same operative team performed the procedure on all animals, and has experience with the same model for a total of more than 100 animals, hemostatic control after the decannulation procedure was believed to be as consistent as possible. Thus variations in postbypass blood loss could be ascribed to pharmacologic effects rather than technical differences. The standard deviation bars shown in the blood loss data show intragroup consistency, which would not be expected if inconsistencies in hemostatic control were a confounding factor. The abdomen was opened after thorough suctioning of the chest, and adrenal and kidney tissue samples were collected and placed in formalin for pathologic examination for microscopic thrombus formation.
Blood samples obtained throughout the procedure were analyzed for hematocrit, platelet count, fibrinogen, celite activated clotting time (ACT), and whole-blood activated partial thromboplastin time (APTT). Plasma aliquots were kept at 4°C until frozen (-70°C) for analysis the following day. Coagulation testing on these samples included prothrombin time, APTT, and anti-IIa activity. Periodic arterial blood samples were obtained for blood gas analysis to guide adjustments in bypass circuit and ventilator settings and bicarbonate administration. Buccal mucosa bleeding times were also obtained at baseline, immediately after the start of the bypass period, immediately after decannulation at the end of CPB, and within 10 to 20 minutes of the start of the observation period. The bypass circuit filters were analyzed for protein deposits using the Folin-Ciocalteu phenol fibrinogen/protein assay.
These studies were conducted in the Animal Research Facilities of Hines VA Hospital (Hines, IL), which is accredited by the American Association for the Accreditation of Laboratory Animal Care. Results are reported as mean ± 1 standard error of the mean. Statistical analyses were performed using the Student's t test; p < 0.05 was considered significant.
|
Results
|
|---|
The results of ACT with conventional heparin treatment with and without aprotinin (Fig 1A
) were comparable to those observed in the clinical situation. The ACT rose rapidly with heparin administration and was maintained at elevated levels until neutralization with protamine at the end of bypass, with a resultant rapid decline to baseline (n = 10). With the same heparin dosage, the addition of aprotinin resulted in consistently higher ACT levels (n = 7). In the case of LMW heparin (Fig 1B), ACT levels were comparable to those determined previously to reflect adequate anticoagulation for CPB in this model (n = 6) [5]. The ACT levels with LMW heparin were not measurably affected by the addition of aprotinin (n = 8), however, in contrast to the effect noted when UF heparin was used as the anticoagulant agent. When r-hirudin was used as the anticoagulant agent, ACT levels both with (n = 8) and without (n = 10) aprotinin (Fig 1C) were beyond the limit of detection of the assay (800 seconds), so it is not possible to determine whether aprotinin made any measurable difference in this assay when r-hirudin was used.
View larger version (16K):
[in this window]
[in a new window]
|
Fig 1. . Celite activated clotting time (ACT) response during CPB with (diamonds) and without (circles) aprotinin for heparin (A), LMW heparin (B), and r-hirudin (C).
|
|
Conventional heparin treatment to the level required for CPB resulted in an APTT level beyond the limit of detection of the assay, both with and without aprotinin (Fig 2A). In the case of LMW heparin also (Fig 2B), the addition of aprotinin significantly increased the APTT. When r-hirudin was used as the anticoagulant agent, many of the data points during the period of bypass were beyond the detection limits of the assay, both with and without aprotinin (Fig 2C). When the mean APTT level was within the limits of the assay, aprotinin did not appear to affect the APTT; this was particularly evident as the APTT results declined after cessation of the infusion of hirudin.
View larger version (17K):
[in this window]
[in a new window]
|
Fig 2. . Whole-blood activated partial thromboplastin time (APTT) response during CPB with (diamonds) and without (circles) aprotinin for heparin (A), LMW heparin (B), and r-hirudin (C). *p < 0.05 versus nonaprotinin group.
|
|
The anti-IIa assay is a chromogenic assay that gives results in terms of percentage inhibition of thrombin. The reference curve is sigmoidal, and it is necessary to dilute samples in many cases so that the result falls within the straight-line portion of the curve. The resultant percentage inhibition is then multiplied by the inverse of the dilution factor, so the result may be well over 100% relative thrombin inhibition, reflecting an excess of anti-IIa activity (r-hirudin or heparin) beyond that needed to neutralize all of the thrombin in the assay. The results with heparin anticoagulation demonstrated a consistent early rise to 200% to 300% relative inhibition, a plateau phase at the 100% to 200% level, and a rapid drop to 0 with protamine administration (Fig 3A). The narrow range of standard error in the figure demonstrates the consistency of the anti-IIa results. Addition of aprotinin did not result in any significant difference in this assay with UF heparin. When LMW heparin was the anticoagulant agent (Fig 3B), anti-IIa levels reached a maximum under 100% relative inhibition, remained at the same level during bypass, and then slowly declined (protamine was not given to animals that received LMW heparin). This assay proved to be the most useful for assessment of anticoagulation with r-hirudin, as noted previously in this CPB model [6]. The anti-IIa level was consistently lower when aprotinin was added (Fig 3C); individual data points did not show statistically significant differences but the curves were virtually parallel, with the aprotinin curve consistently lower than the control curve.
View larger version (17K):
[in this window]
[in a new window]
|
Fig 3. . Response of the anti-factor IIa assay during CPB with (diamonds) and without (circles) aprotinin for heparin (A), LMW heparin (B), and r-hirudin (C).
|
|
Figure 4 depicts the blood loss, in mL/kg, during the 2-hour post-bypass observation period. The blood lost during the bypass period was not included because, as mentioned previously, variations in blood lost during cannulation and decannulation were due to technical operative differences among the subjects rather than pharmacologic effects, and after decannulation, gross bleeding was variable until control was obtained. The drug effects on post-bypass oozing of blood was the area of interest after all operative bleeding had been brought under control. As expected, when UF heparin was the anticoagulant agent, blood loss was reduced significantly by the addition of aprotinin, and the reduction (9.3 ± 1.3 mL/kg without aprotinin versus 4.8 ± 0.8 mL/kg with aprotinin; p < 0.05) was consistent with the clinical observations. On the other hand, when LMW heparin and r-hirudin were used as anticoagulant agents, blood loss was not significantly different upon aprotinin administration.
View larger version (23K):
[in this window]
[in a new window]
|
Fig 4. . Postoperative (2 hour) blood loss for aprotinin (shaded bars) and nonaprotinin (open bars) groups for each of the three anticoagulant agents. *p < 0.05 versus nonaprotinin group. (LMWH = low molecular weight heparin.)
|
|
Measurement of protein deposition on the bypass circuit arterial filters (Fig 5) showed a reduction in filter deposits in the aprotinin groups with all anticoagulant agents. The differences were not statistically significant in the heparin and r-hirudin groups, but were significant in the LMW heparin group (32.5 ± 9.3 mg without aprotinin versus 1.6 ± 0.8 mg with aprotinin; p < 0.05).
View larger version (26K):
[in this window]
[in a new window]
|
Fig 5. . Protein deposition in the arterial line filters after CPB for aprotinin (shaded bars) and nonaprotinin (open bars) groups for each of the three anticoagulant agents. *p < 0.05 versus nonaprotinin group. (LMWH = low molecular weight heparin.)
|
|
Pathologic examination of kidney and adrenal tissue samples showed no microthrombi in samples from any subject, indicating the adequacy of anticoagulation in all cases and the absence of any deleterious prothrombotic effects of aprotinin at the level of anticoagulation required for CPB.
|
Comment
|
|---|
The addition of aprotinin resulted in a significant decrease in blood loss only in those animals that received anticoagulation with UF heparin. In the r-hirudin group, blood loss was only slightly lower, and not to a statistically significant degree, when aprotinin was used. When LMW heparin was used for anticoagulation, the addition of aprotinin resulted in a slightly greater degree of blood loss.
The effects of aprotinin appear to be mediated primarily through preservation of platelet GPIb receptors [7, 8] and inhibition of plasmin activity, both directly and through inhibition of kallikrein [2, 8, 9–11]. These factors, however, would be expected to be operational with all of the three anticoagulant agents tested in this study. Thus, the observed failure of aprotinin to reduce blood loss significantly when LMW heparin and r-hirudin were used must be due to differing mechanisms of action of the anticoagulant agents or differences in their interactions with aprotinin.
One interesting possibility involves the regulation of coagulation by protein C, which affects the intrinsic clotting mechanism through inactivation of factor VIIIa as well as the common pathway through inactivation of factor Va. Protein C also promotes fibrinolysis through inactivation of plasminogen activator inhibitor-1 and -3. Espana and associates [12] found that aprotinin inhibited activated protein C and that heparin increased the affinity of aprotinin for protein C in a dose-dependent manner. Aprotinin therefore reduces the anticoagulant and fibrinolytic activities of protein C, and this effect of aprotinin is enhanced by the presence of UF heparin. The possibility of interaction of LMW heparin or r-hirudin with protein C has not been addressed, although it is unlikely considering the structural dissimilarities among the three agents.
Another possible explanation for the observed differences in the effects of aprotinin on blood loss may involve the nature of hemostatic clots formed and their interaction with the anticoagulant agents. According to Mirshahi and colleagues [11], UF heparin induces a significant increase in the retention of platelets in whole blood clot, whereas LMW heparin does not exhibit this effect. Clots rich in platelets were found to be resistant to thrombolysis [11]. Although the presence or absence of an effect of r-hirudin on the retention of platelets in clots has not been addressed, it is known that hirudin is able to inhibit clot-bound thrombin and has little or no effect on platelets except through its effects on thrombin [13].
A direct effect on platelet function also may account for the interaction of UF heparin and aprotinin. Unfractionated heparin is associated with inhibition of platelet function that may be reversed by aprotinin, possibly because of similarities in binding of UF heparin and aprotinin to platelets with a competition for binding sites, such that binding of UF heparin is reduced in the presence of aprotinin [14]. The assumption, of course, is that LMW heparin and r-hirudin do not compete with aprotinin in a similar manner, a matter that has not been investigated.
Although aprotinin significantly lowered blood loss with heparin anticoagulation, it did not increase filter deposits, and in fact slightly reduced clots. In the case of r-hirudin, filter deposits were lowered, though not significantly, with the addition of aprotinin. However, when LMW heparin was the anticoagulant agent, the addition of aprotinin resulted in a striking decrease in filter deposits. The observed effects are most likely secondary to the particular mechanisms of action of the anticoagulant agents and their interactions with the anticoagulant effects of aprotinin. Although aprotinin's inhibition of thrombin may be additive to the anti-IIa (thrombin) activities of UF heparin and r-hirudin, the high dosage of these agents used in CPB may leave little thrombin available for inhibition by aprotinin. In contrast, aprotinin inhibition of thrombin may become more important when LMW heparin is the anticoagulant agent, and a strong synergistic effect may result from the inhibition of factor Xa by LMW heparin along with thrombin inhibition by both agents. Another possibility involves, again, the interaction of aprotinin with the protein C system. Factor Xa requires factor Va as a cofactor for efficient function. Protein C exerts its anticoagulant effect through inactivation of factors Va and VIIIa. By inhibiting protein C, aprotinin preserves factor Va and thereby the efficient function of factor Xa. Of the three anticoagulant agents evaluated, LMW heparin is most dependent on the anti-Xa activity and therefore the strongest counteraction to this particular procoagulant effect of aprotinin.
The elevation of the celite ACT by aprotinin during anticoagulation with UF heparin is in agreement with other studies, as well as clinical observations [9, 15]. The ACT level of the LMW heparin control was clearly lower than that observed for UF heparin without elevation by aprotinin. This lower effect reflects the fact that the celite ACT is an in vitro test of anticoagulation that is meaningful only in terms of its relation to an established effective level of in vivo antithrombotic activity. Aprotinin clearly affects the ACT in a different manner when the anticoagulant agent is UF heparin as compared with LMW heparin. A possible explanation was raised by the work of deSmet and co-workers [15], who postulated that because the ACT becomes highly sensitive to platelet function at heparin doses used during CPB, the elevation observed with aprotinin may be due to inhibition of platelet aggregation. Thrombin-induced platelet aggregation has been shown to be inhibited by aprotinin [9, 14, 16]. Beumer and colleagues [17] demonstrated a 12-fold greater sensitivity to UF heparin than to LMW heparin in inhibition of platelet adhesion to fibronectin. These effects were found in their study to be mediated by the GPIIb/IIIa receptor, which binds fibronectin and which is also a component in platelet aggregation. Therefore, aprotinin may exhibit a synergistic inhibition of platelet aggregation when added to heparin-treated blood that is not observed when anticoagulation is with LMW heparin. No conclusion could be drawn as to whether the ACT was affected by aprotinin when r-hirudin was the anticoagulant agent because the results were beyond the limits of detection of the assay in both the control and aprotinin groups.
The APTT assay demonstrated an effect of aprotinin only with LMW heparin. A possible explanation is a synergism between aprotinin's kallikrein inhibition and the factor Xa inhibition characteristic of LMW heparin. The LMW heparin controls demonstrated measurable end points, whereas the 300-second limit of the assay was approached with the addition of aprotinin. In contrast, UF heparin and r-hirudin controls were beyond the detection limits of the assay, so the effects of addition of aprotinin were impossible to gauge.
The chromogenic anti-IIa assay is a selective measure of antithrombin activity. In the UF heparin and LMW heparin groups, anti-IIa levels were not measurably affected by the addition of aprotinin. The absolute levels of anti-IIa activity reflect the difference in mechanism of action of LMW heparin as compared with UF heparin. The findings in the case of r-hirudin are interesting in that the anti-IIa levels in the presence of aprotinin were consistently lower than those of controls during the period of r-hirudin administration. Although standard errors precluded statistically significant differences in individual data points, there was an apparent trend of aprotinin toward reducing the antithrombin activity in hirudin-treated blood. It is possible that competition by aprotinin for the binding site on thrombin maintains a higher level of free hirudin, with a resultant increase in the rate of hirudin elimination and consequently lower anti-IIa levels in samples.
This study demonstrates that the beneficial effects of aprotinin with respect to blood loss after CPB observed with heparin anticoagulation cannot be presumed to occur when alternative anticoagulant agents are used. The reasons for these observations, however, are far from clear. This is not surprising in light of the controversies regarding the mechanism of dysfunction due to extracorporeal circulation, the mechanism of action of aprotinin in CPB, the broad serine protease activities of aprotinin, and the complex homeostatic system that incorporates hemostasis, fibrinolysis, the complement pathway, kinins, and the interaction of this system with platelets and other cellular elements. Many questions remain to be answered regarding aprotinin's interactions with these systems. Successfully addressing these questions may lead to other pharmacologic interventions that may be able to achieve the blood preservation effect of aprotinin when anticoagulant agents other than heparin are used for CPB.
|
Acknowledgments
|
|---|
We express our sincere gratitude to Nicholas King, CCP, for perfusion and animal model skills and to Areta Kowal-Vern, MD, for expert histologic tissue analyses.
|
Footnotes
|
|---|
Address reprint requests to Dr Walenga, Cardiovascular Institute, Loyola University Medical Center, 2160 S. First Ave, Maywood, IL 60153.
|
References
|
|---|
- Levy JH, Pifarre R, Schaff HV, et al. A multicenter, double-blind, placebo-controlled trial of aprotinin for reducing blood loss and the requirement for donor-blood transfusion in patients undergoing repeat coronary artery bypass grafting. Circulation 1995;92:2236–44.[Abstract/Free Full Text]
- Blauhut B, Gross C, Necek S, Doran JE, Spath P, Lundsgaard-Hansen P. Effects of high-dose aprotinin on blood loss, platelet function, fibrinolysis, complement, and renal function after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1991;101:958–67.[Abstract]
- Cosgrove DM III, Heric B, Lytle BW, et al. Aprotinin therapy for reoperative myocardial revascularization: a placebo-controlled study. Ann Thorac Surg 1992;54:1031–8.[Abstract]
- Koza MJ, Messmore HL, Wallock ME, Walenga JM, Pifarre R. Evaluation of a low molecular weight heparin as an anticoagulant in a model of cardiopulmonary bypass surgery. Thromb Res 1993;70:67–76.[Medline]
- Walenga JM, Koza M, Park S, et al. Can heparin be replaced by LMW heparin in cardiopulmonary bypass surgery? Thromb Haemost 1993;69:935.
- Walenga JM, Koza MJ, Park SJ, Terrell MR, Pifarre R. Evaluation of CGP 39393 as the anticoagulant in cardiopulmonary bypass operation in a dog model. Ann Thorac Surg 1994;58:1685–9.[Abstract]
- Wachtfogel YT, Kucich U, Hack CE, et al. Aprotinin inhibits the contact, neutrophil and platelet activation systems during simulated extracorporeal perfusion. J Thorac Cardiovasc Surg 1993;106:1–10.[Abstract]
- Huang H, Ding W, Su Z, Zhang W. Mechanism of the preserving effect of aprotinin on platelet function and its use in cardiac surgery. J Thorac Cardiovasc Surg 1993;106:11–8.[Abstract]
- Najman DM, Walenga JM, Fareed J, Pifarre R. Effects of aprotinin on anticoagulant monitoring: implications in cardiovascular surgery. Ann Thorac Surg 1993;55:662–6.[Abstract]
- Gallimore MJ, Heller W, Fuhrer G, Wendel H, Klaffschenkel R, Hoffmeister HE. Contact activation, heparins and cardiopulmonary bypass. Thromb Haemost 1992;68:91–2.[Medline]
- Mirshahi MC, Soria J, Neuhart E, et al. Effect of heparin and Enoxaparin on platelet interaction with fibrin clots. Thromb Res 1992;65:187–91.[Medline]
- Espana F, Estelles A, Griffin JH, Aznar J, Gilabert J. Aprotinin (Trasylol) is a competitive inhibitor of activated protein C. Thromb Res 1989;56:751–6.[Medline]
- Markwardt F. Hirudin: the famous anticoagulant agent. In: Claeson G, Scully MF, Kakkar W, Deadman J, eds. The design of synthetic inhibitors of thrombin. New York: Plenum Press, 1993:191–211.
- John LCH, Rees GM, Kovacs IB. Reduction of heparin binding to and inhibition of platelets by aprotinin. Ann Thorac Surg 1993;55:1175–9.[Abstract]
- De Smet AAEA, Joen MCN, van Oeveren W, et al. Increased anticoagulation during cardiopulmonary bypass by aprotinin. J Thorac Cardiovasc Surg 1990;100:520–7.[Abstract]
- Pintigny D, Dachary-Prigent J. Aprotinin can inhibit the proteolytic activity of thrombin. A fluorescence and an enzymatic study. Eur J Biochem 1992;207:89–95.[Medline]
- Beumer S, Ijsseldijk MJW, de Groot PG, Sixma JJ. Platelet adhesion to fibronectin in flow: dependence on surface concentration and shear rate, role of platelet membrane glycoproteins GPIIb/IIIa and VLA-5, and inhibition by heparin. Blood 1994;84:3724–33.[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
M. Wallock, W. P Jeske, M. Bakhos, and J. M Walenga
Evaluation of a new point of care heparin test for cardiopulmonary bypass: the TAS heparin management test
Perfusion,
March 1, 2001;
16(2):
147 - 153.
[Abstract]
[PDF]
|
|
|
|
|
|
|
T. P. Carrel, M. Schwanda, P. R. Vogt, and M. I. Turina
Aprotinin in pediatric cardiac operations: a benefit in complex malformations and with high-dose regimen only
Ann. Thorac. Surg.,
July 1, 1998;
66(1):
153 - 158.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction
