- Email: [email protected]
Anticoagulation
Panel II
Anticoagulation Moderator: Jack G. Copeland 111, MD Panelists: 0. H. Frazier, MD, Lawrence R. McBride, MD, Marko I. Turina, MD, and Christian Cabrol, MD MODERATOR COPELAND: I think that we cannot really discuss anticoagulation without discussing hemostasis and bleeding with circulatory support devices. I would like to make a few comments before we proceed with our panel members. One thing we know for sure about our experiences with these devices is that the device interface with blood provides a constant source of stimulation of the platelet system and the clotting system. Sites of thrombus formation that have been reported include inlet and outlet cannulas, valves and valve mounts, housings, diaphragms, and the like. We have looked at platelet metabolism and found that platelets are continuously activated, presumably by their contact with the device. And if one looks serially at the /3-thromboglobulin level, it is elevated. There is a continuous stimulation of fibrin metabolism. There is fibrin formation indicated by the persistent evaluation of fibrinopeptide A. Evidence of fibrinolysis in the form of XDP or cross-linked fibrin degradation products is also present. Prevention of thrombus formation remains a problem. In 1985 we reported valve mount crevice thrombus in the Jarvik total artificial heart, and we have also seen small foci of platelet aggregations on a housing of biventricular assist devices. We use a fairly standard anticoagulation regimen for the total artificial heart, biventricular assist devices, and the Novacor left ventricular assist system. On the first postoperative day we start administration of dextran 40 at 25 mL/h and we give dipyridamole, 75 to 100 mg every 6 hours through the nasogastric tube or orally. Starting on the second postoperative day we begin administration of heparin and we maintain a partial thromboplastin time of 50 10 seconds and continue the dipyridamole. By about the fifth to seventh postoperative day we switch from continuous heparin infusion to warfarin sodium, and we maintain a prothrombin time of about 18 & 2 seconds. We continue dipyridamole administration. Any patient who has an episode that might be interpreted as a neurologic problem, for instance a transient ischemic attack, receives aspirin, 325 mg per day. Finally, I would like to mention hemorrhage. We preclot the inflow and outflow grafts three times before heparinization. This takes about 20 to 30 minutes. Then we spray the outside of these grafts with biologic glue. Since doing that we have not had any serious graft hemorrhage. Before the use of this technique we commonly observed hemorrhage through the interstices of
*
Presented at the Circulatory Support 1991 Symposium of The Society of Thoracic Surgeons, San Francisco, CA, Nov 1617, 1991.
0 1993 by The Society of Thoracic Surgeons
the outflow (high pressure) graft. Thus, anticoagulation problems that I hope we will discuss today include hemorrhage, one of the major problems with each device. I think it is common, and seen in up to 30% of implants. It is often massive, resulting in tamponade. Tamponade may also occur late, weeks after implantation. I hope we will also focus on thromboembolism. If one looks, for instance, at the total artificial heart data, less than 10% of patients have embolic neurologic events and 5% have strokes with permanent neurologic damage. This may be less thromboembolism than we feared 5 years ago, but clearly there is room for improvement. To lead off I would like to ask Dr Frazier to talk. His experience has been primarily with the TCI device.
DR FRAZIER The main problem in research in this area is the blood-biomaterial interface. We have to be concerned about that interface with any of this technology. The TCI device is designed to be minimally thrombogenic, so we have never been forced to deal with problems of clotting as much as bleeding. Bleeding has been a much greater problem than thrombus formation. Of course we completely reverse the protamine at the close of the operation, and we give no anticoagulant until the patient’s condition is stabilized in the intensive care unit. At a convenient point we then start the patient on low molecular weight dextran, which is what we also use for intraaortic balloon pumps. And when the patient is taking oral feedings we start administration of dipyridamole and a low dose of acetylsalicylic acid. We really do not use heparin in the postoperative period unless the pump stroke volume becomes very low. The lining of this pump housing is titanium microspheres. The pumping diaphragm, however, is an integrally textured polyurethane surface, which allows blood elements to catch very early on this lining. On a diaphragm taken from a 41-day patient, cells are present on the surface of the pump housing and pumping diaphragm. In a patient who has had the pump in place more than 200 days we have seen a very smooth surface with no calcification and with some endothelial cells on the surface. As far as I know, that is the first demonstration of endothelial cells cultured from an artificial surface in humans. As you know it has previously been achieved in pigs and dogs, but not in humans. These cells must be coming from the circulating blood cells. A great advantage of this pump to date is that in more than 6 years of total use we have had only one episode of thromboembolic problems. That problem was that the Ann Thorac Surg 1993;55:21M
0003-4975/93/$6.00
214
CIRCULATORY SUPPORT ANTICOAGULATION
PANEL I1
Ann Thorac Surg 1993;55:213-6
inflow cannula was kinked, leading to a distortion of the diastolic blood flow and a thromboembolic event at a little more than 100 days. But I feel very safe with this low level of anticoagulation with this regimen. We have done away with the blood-biomaterial interface.
MODERATOR COPELAND: Next we have Lawrence McBride from St. Louis University, who is going to tell us about their experience with anticoagulation. DR McBRIDE: At St. Louis University we have used three different types of pulsatile ventricular assist devices: the Thoratec pump, the Novacor and Jarvik artificial heart. Our anticoagulation regimen in all these patients consists of starting them on dextran at 25 mL/h as soon as their chest tube drainage falls to less than 100 mWh for 3 consecutive hours. In the interim we try to correct any coagulation abnormalities by infusing fresh frozen plasma as well as platelets as necessary. Once the coagulation parameters have been normalized, we start the patients on intravenous heparin at 10 U kg-' h-' and we adjust the dose to maintain a partial thromboplastin time of 1% times normal. When the patients are extubated, and they start on oral intake, warfarin sodium is added and we attempt to achieve a prothrombin time of 1%times the normal. We do not wean the heparin until the prothrombin time is 1% times control, what we consider to be the therapeutic range. We add aspirin, 75 mg per day, only if the patient has had a thromboembolic event, or we believe that the patient is at high risk for this, such as an individual who was supported with a device who also may have a prosthetic valve in place. As we have heard throughout the morning, bleeding is a major problem in this group of patients. Of 80 patients who were supported with devices, 42 had the device inserted with the intent that their heart would recover, and 38 patients had the device inserted as a bridge to transplantation. As one would expect, the postcardiotomy group had more bleeding and required more blood products than the bridge to transplantation group. Blood losses at 48 hours were significantly different because of wide variance from the mean. Overall, 24 of our patients required reexploration. Over the last 40, however, only 8 patients have required reexploration as we have paid more attention to correcting any coagulation abnormalities and also we have improved our operative technique, especially with clotting the graft as Dr Copeland had mentioned. As one would expect, our survivors bled less than our nonsurvivors. However this was only statistically significant in the bridge to transplantation group. In our recovery group most of these patients died of myocardial failure with multiple organ failure. Another major problem that these patients have is thrombus in the pump or systemic embolization. In our Thoratec group of 94 devices that were explanted we found evidence of either red cell or platelet thrombus in the system of 10 patients. Nine of these patients had predisposing factors. However, 4 of the patients had mechanical disruption of their flow for a period of time. Three of the patients had major gastrointestinal bleeding,
-
-
which required discontinua tion of their anticoagulation for a few days, and 2 patients had severe septic episodes. In addition to this group we had 9 patients who had either clinical evidence or postmortem evidence of having a systemic embolization. We did not find any thrombi in the nine Novacor sacs that were removed. However, 1 of our patients did have a cerebral embolus several days after implantation. This patient had multiple organ failure, had a few episodes of sepsis, and also had a serious gastrointestinal bleed for which anticoagulation was discontinued. Interestingly, 3 of these patients had pseudoneointimal formation in the conduit, a thin layer of collagen that lined the graft. It was adherent to the graft, and we are not aware of it having caused any problems for the patients. We had 2 patients who were supported with the Jarvik heart, and we found thrombus in one of these pumps. However, unfortunately both patients had clinical cerebral embolizations.
MODERATOR COPELAND: Our next speaker is going to deviate a little bit, I believe, from what you have heard from the last three. He is Dr Marko Turina from Zurich, Switzerland, who has had extensive experience with the Carmeda process cardiopulmonary bypass, and he is going to tell us a little bit about that. DR TURINA: I would like to tell you about the work we have been doing in Zurich and that has been taking place in Europe working with heparin attached to the parts of the pump oxygenator system and of the assist devices. There are numerous advantages if you are able to attach heparin reliably to the surfaces and not systemically heparinize the patient, or use less heparin. Of course during cardiopulmonary bypass it will reduce the blood loss. You will have less blood transfused; consequently, it will shorten the operating time. But the additional effect, which we do not know very much about, involves less complement activation and modifying immunologic response and having less anaphylactic reaction from the protamine, which can be a problem. Decreased stimulation from heparinized surfaces may decrease generation of free radicals, hemolysis, and the neutrophil activation. We have been using in the last 3% years both ionic fixation and end-point fixation of heparin in the tubing and the Maxima Medtronic oxygenator with the Carmeda. We have also had coated surfaces in the Bio-Medicus pump. We have performed a prospective, randomized study which was conducted by Dr Franz Agasa, who has done most of this experimental work and has been in charge of the clinical evaluation of this work. We used the Carmeda system in a prospective, randomized way for coronary revascularization. We used the same oxygenator in both groups, giving the group with the low heparinization 100 U/kg and the full heparinization 300 U k g . We maintained the activated clotting time during revascularization procedures of the low group greater than 180 seconds. We were not courageous enough to completely eliminate heparin. I think we will always need some heparin. In the other group the activated clotting time was
Ann Thorac Surg 1993;55:21M
kept about 480 seconds. We were able to grossly reduce, in a statistically significant way, the loss of blood and the amount of blood transfused. Half of the patients did not need any transfusions whatsoever. So the first clinical trial has shown that blood loss can be reduced and less blood is transfused. This was significant. We found no other significant differences. The second clinical trial used the Carmeda system devices on the roller pump and on the centrifugal pump for the resection of thoracic aortic aneurysms. Partial cardiopulmonary bypass has taken a lot of problems away when dealing with a big thoracic aneurysm, especially those extending below the diaphragm when you have to replace the whole aorta. This is our method of choice now. The only fatality that we had in this group was in a patient with a ruptured thoracic aneurysm, which are rather difficult to deal with as you all know. Of course there is a word of caution about using these heparincoated devices, because you can generate excessive thrombogenicity, and there is a theoretical danger of the closure of the bypass grafts, especially thrombosis of the endarterectomized artery and maybe a thrombus in the mechanical valve prosthesis. We have not observed that, but there is probably a need for a minimal heparinization. We found that thrombosis in the perfusion system may occur with minimal heparinization, and therefore special techniques have to be used to keep the blood moving constantly in the perfusion system. With this technique we have found no evidence of the activation of coagulation cascade.
MODERATOR COPELAND: Finally, Dr Cabrol will give us his vast experience from La Pitie Hospital. DR CABROL In our hospital we are not fortunate enough to have a hematology unit. So we had to engage a colleague, Dr Szefner, who specialized in this work, and this appears to be quite satisfactory. So the total experience is now 58 patients and more than 1,000 patient-days; 1 patient has had more than 600 days on the Jarvik. As our moderator explained, the anticoagulation must prevent many problems that are shared by many devices: fibrinolysis, exacerbation of platelet function, and exaggerated coagulation. We have to stop the fibrinolysis to stabilize the blood and the functions and to balance the coagulations. Fibrinolysis is due to the transformation of plasminogen to plasmin and destruction of fibrinogen and fibrin. To measure the fibrinolysis we have some test of plasminogen and fibrin degradation products. We treat fibrinolysis using aprotinin, one million units in intravenous injection followed by a drip of 4,000 U/min. The second problem is a strong and permanent activation of platelets. To measure this exaggerated platelet activation in vivo we use /3-thromboglobulin, platelet factor IV, and platelet aggregation in vitro. We normalize platelet function using dipyridamole in big doses, 600 to 1,200 mglday. When the platelet function is stabilized we use aspirin in very small doses, 50 to 100 mg a day. The third problem is to reestablish the normal balance between thrombin formation and neutralization by an-
CIRCULATORY SUPPORT PANEL II ANTICOAGULATION
215
tithrombin. To correct this excess of thrombin we use heparin, 1,000 to 5,000 U/day. I must that say we had no biological bleeding in that series. Of course we have some surgical but not biological; that was always controlled by the technique of our colleagues. Also we had only two thromboembolic events, both occurring in our patient who lived 600 days with the Jarvik. She had two small episodes of neurological troubles; they were very transient. Examination of the device after use showed absence of microscopic thrombi in high-risk sites like Dr Copeland said, especially around the valve, and absence of iatrogenic bleeding. Finally, the various alterations in platelet function and coagulation kinetics linked to total artificial heart implantation require permanent anticoagulation and antiaggregation as well as a suitable follow-up. The protocol must be able to explore all the systems involved to modulate treatments to individual needs.
MODERATOR COPELAND: We are open for questions. DR D. GLENN PENNINGTON (St. Louis, MO): I would like to ask Marko Turina a question. Let me give you a situation where you, let us say, have a Bio-Medicus pump and the Carmeda-coated tubing with Carmedacoated cannulas. You have that system ready and you put it in a patient for ventricular support. The question is as follows: How much anticoagulation would you think is necessary? Would you use none? Also, is it necessary to follow up antithrombin I11 levels? And if so, what are your limits? If the antithrombin 111 level falls below a certain level should we give heparin? What advice can you give us? DR TURINA: I do not think that you can eliminate the use of heparin altogether, because there are the vagaries of the implantation and there are times when you are not circulating in your system. There is always the danger of thrombosis. You are also running, especially if the patient has been receiving aprotinin, through some periods when the patient is in a hypercoagulable state. So to answer it simply in a situation like this, yes. We would use the heparinization that is used in vascular surgery just as the minimum heparinization to prevent some of the possible complications. We do not have hard data to prove that, but in the animal experiments when we had been running some of these devices they have been observed without any heparin whatsoever. We observed microemboli, and that is one of the pieces of indirect evidence that some heparin should be used. Only the activated clotting time is monitored. MODERATOR COPELAND: 1 would like to ask Dr Frazier a question. You said that bleeding seemed to be a problem. Is that bleeding device-related or is that related to technique? How would you go about minimizing the bleeding? DR FRAZIER Well, bleeding is a patient-related phenomenon. Actually, in the implantation of these devices
216
CIRCULATORY SUPPORT ANTICOAGULATION
PANEL I1
there is nothing intrinsically about their implantation that contributes a lot to bleeding. Obviously with the total artificial heart implantation there are long suture lines. With the left ventricular assist device, the Novacor and the Thermetics devices, the ventricular attachment is decompressed. There is no pressure. It is a low-pressure line and the aortic suture line is right in front of you. We use a woven graft and have never really had problems with the graft bleeding. So the bleeding that we have encountered has been from patients with advanced, longstanding heart failure or hepatic dysfunction; particularly more recently, patients on prolonged Inocor support with accompanying platelet dysfunction have just been a coagulation nightmare. And the bleeding is the problem, not clotting. MODERATOR COPELAND: So you treat the coagulopathy? DR FRAZIER I do. I wish we had access to aprotinin because it does seem that it might help with these difficult patients. MODERATOR COPELAND: Doctor McBride, you talked about pseudoneointima. How long had those grafts been implanted? Do you think that duration of implantation has something to do with the presence of pseudoneointima?
Ann Thorac Surg 1993;55:213&
DR McBRIDE: The longest patient had it implanted for more than a year, and he had this fine membrane that lined the graft and was densely adherent to the graft, which did not cause a problem with the function of the device at all. The other 2 patients, if I am not mistaken, had the device in for more than a month. DR MICHAEL ALIER (Houston, TX): I do not want to belabor a point, but what about heparin-induced thrombocytopenia in this whole group of patients who are intermittently on lots of heparin a long time? MODERATOR COPELAND: In our own experience that is one of the reasons we try to get off. In addition, we have had trouble keeping patients even on continuous heparin infusions because of oscillation of partial thromboplastin times. That is why we tend to move on to warfarin sodium fairly quickly. Dr Cabrol, have you had any trouble with that? You keep your patients continuously on heparin for the entire time that they have the device in place. Do you ever see falls in platelet counts or do you have trouble with using heparin? DR CABROL Well, no. So far we do not have any problems. We use heparin intravenously for some days, and after that we use subcutaneous heparin.
Anticoagulation Moderator: Jack G. Copeland 111, MD Panelists: 0. H. Frazier, MD, Lawrence R. McBride, MD, Marko I. Turina, MD, and Christian Cabrol, MD MODERATOR COPELAND: I think that we cannot really discuss anticoagulation without discussing hemostasis and bleeding with circulatory support devices. I would like to make a few comments before we proceed with our panel members. One thing we know for sure about our experiences with these devices is that the device interface with blood provides a constant source of stimulation of the platelet system and the clotting system. Sites of thrombus formation that have been reported include inlet and outlet cannulas, valves and valve mounts, housings, diaphragms, and the like. We have looked at platelet metabolism and found that platelets are continuously activated, presumably by their contact with the device. And if one looks serially at the /3-thromboglobulin level, it is elevated. There is a continuous stimulation of fibrin metabolism. There is fibrin formation indicated by the persistent evaluation of fibrinopeptide A. Evidence of fibrinolysis in the form of XDP or cross-linked fibrin degradation products is also present. Prevention of thrombus formation remains a problem. In 1985 we reported valve mount crevice thrombus in the Jarvik total artificial heart, and we have also seen small foci of platelet aggregations on a housing of biventricular assist devices. We use a fairly standard anticoagulation regimen for the total artificial heart, biventricular assist devices, and the Novacor left ventricular assist system. On the first postoperative day we start administration of dextran 40 at 25 mL/h and we give dipyridamole, 75 to 100 mg every 6 hours through the nasogastric tube or orally. Starting on the second postoperative day we begin administration of heparin and we maintain a partial thromboplastin time of 50 10 seconds and continue the dipyridamole. By about the fifth to seventh postoperative day we switch from continuous heparin infusion to warfarin sodium, and we maintain a prothrombin time of about 18 & 2 seconds. We continue dipyridamole administration. Any patient who has an episode that might be interpreted as a neurologic problem, for instance a transient ischemic attack, receives aspirin, 325 mg per day. Finally, I would like to mention hemorrhage. We preclot the inflow and outflow grafts three times before heparinization. This takes about 20 to 30 minutes. Then we spray the outside of these grafts with biologic glue. Since doing that we have not had any serious graft hemorrhage. Before the use of this technique we commonly observed hemorrhage through the interstices of
*
Presented at the Circulatory Support 1991 Symposium of The Society of Thoracic Surgeons, San Francisco, CA, Nov 1617, 1991.
0 1993 by The Society of Thoracic Surgeons
the outflow (high pressure) graft. Thus, anticoagulation problems that I hope we will discuss today include hemorrhage, one of the major problems with each device. I think it is common, and seen in up to 30% of implants. It is often massive, resulting in tamponade. Tamponade may also occur late, weeks after implantation. I hope we will also focus on thromboembolism. If one looks, for instance, at the total artificial heart data, less than 10% of patients have embolic neurologic events and 5% have strokes with permanent neurologic damage. This may be less thromboembolism than we feared 5 years ago, but clearly there is room for improvement. To lead off I would like to ask Dr Frazier to talk. His experience has been primarily with the TCI device.
DR FRAZIER The main problem in research in this area is the blood-biomaterial interface. We have to be concerned about that interface with any of this technology. The TCI device is designed to be minimally thrombogenic, so we have never been forced to deal with problems of clotting as much as bleeding. Bleeding has been a much greater problem than thrombus formation. Of course we completely reverse the protamine at the close of the operation, and we give no anticoagulant until the patient’s condition is stabilized in the intensive care unit. At a convenient point we then start the patient on low molecular weight dextran, which is what we also use for intraaortic balloon pumps. And when the patient is taking oral feedings we start administration of dipyridamole and a low dose of acetylsalicylic acid. We really do not use heparin in the postoperative period unless the pump stroke volume becomes very low. The lining of this pump housing is titanium microspheres. The pumping diaphragm, however, is an integrally textured polyurethane surface, which allows blood elements to catch very early on this lining. On a diaphragm taken from a 41-day patient, cells are present on the surface of the pump housing and pumping diaphragm. In a patient who has had the pump in place more than 200 days we have seen a very smooth surface with no calcification and with some endothelial cells on the surface. As far as I know, that is the first demonstration of endothelial cells cultured from an artificial surface in humans. As you know it has previously been achieved in pigs and dogs, but not in humans. These cells must be coming from the circulating blood cells. A great advantage of this pump to date is that in more than 6 years of total use we have had only one episode of thromboembolic problems. That problem was that the Ann Thorac Surg 1993;55:21M
0003-4975/93/$6.00
214
CIRCULATORY SUPPORT ANTICOAGULATION
PANEL I1
Ann Thorac Surg 1993;55:213-6
inflow cannula was kinked, leading to a distortion of the diastolic blood flow and a thromboembolic event at a little more than 100 days. But I feel very safe with this low level of anticoagulation with this regimen. We have done away with the blood-biomaterial interface.
MODERATOR COPELAND: Next we have Lawrence McBride from St. Louis University, who is going to tell us about their experience with anticoagulation. DR McBRIDE: At St. Louis University we have used three different types of pulsatile ventricular assist devices: the Thoratec pump, the Novacor and Jarvik artificial heart. Our anticoagulation regimen in all these patients consists of starting them on dextran at 25 mL/h as soon as their chest tube drainage falls to less than 100 mWh for 3 consecutive hours. In the interim we try to correct any coagulation abnormalities by infusing fresh frozen plasma as well as platelets as necessary. Once the coagulation parameters have been normalized, we start the patients on intravenous heparin at 10 U kg-' h-' and we adjust the dose to maintain a partial thromboplastin time of 1% times normal. When the patients are extubated, and they start on oral intake, warfarin sodium is added and we attempt to achieve a prothrombin time of 1%times the normal. We do not wean the heparin until the prothrombin time is 1% times control, what we consider to be the therapeutic range. We add aspirin, 75 mg per day, only if the patient has had a thromboembolic event, or we believe that the patient is at high risk for this, such as an individual who was supported with a device who also may have a prosthetic valve in place. As we have heard throughout the morning, bleeding is a major problem in this group of patients. Of 80 patients who were supported with devices, 42 had the device inserted with the intent that their heart would recover, and 38 patients had the device inserted as a bridge to transplantation. As one would expect, the postcardiotomy group had more bleeding and required more blood products than the bridge to transplantation group. Blood losses at 48 hours were significantly different because of wide variance from the mean. Overall, 24 of our patients required reexploration. Over the last 40, however, only 8 patients have required reexploration as we have paid more attention to correcting any coagulation abnormalities and also we have improved our operative technique, especially with clotting the graft as Dr Copeland had mentioned. As one would expect, our survivors bled less than our nonsurvivors. However this was only statistically significant in the bridge to transplantation group. In our recovery group most of these patients died of myocardial failure with multiple organ failure. Another major problem that these patients have is thrombus in the pump or systemic embolization. In our Thoratec group of 94 devices that were explanted we found evidence of either red cell or platelet thrombus in the system of 10 patients. Nine of these patients had predisposing factors. However, 4 of the patients had mechanical disruption of their flow for a period of time. Three of the patients had major gastrointestinal bleeding,
-
-
which required discontinua tion of their anticoagulation for a few days, and 2 patients had severe septic episodes. In addition to this group we had 9 patients who had either clinical evidence or postmortem evidence of having a systemic embolization. We did not find any thrombi in the nine Novacor sacs that were removed. However, 1 of our patients did have a cerebral embolus several days after implantation. This patient had multiple organ failure, had a few episodes of sepsis, and also had a serious gastrointestinal bleed for which anticoagulation was discontinued. Interestingly, 3 of these patients had pseudoneointimal formation in the conduit, a thin layer of collagen that lined the graft. It was adherent to the graft, and we are not aware of it having caused any problems for the patients. We had 2 patients who were supported with the Jarvik heart, and we found thrombus in one of these pumps. However, unfortunately both patients had clinical cerebral embolizations.
MODERATOR COPELAND: Our next speaker is going to deviate a little bit, I believe, from what you have heard from the last three. He is Dr Marko Turina from Zurich, Switzerland, who has had extensive experience with the Carmeda process cardiopulmonary bypass, and he is going to tell us a little bit about that. DR TURINA: I would like to tell you about the work we have been doing in Zurich and that has been taking place in Europe working with heparin attached to the parts of the pump oxygenator system and of the assist devices. There are numerous advantages if you are able to attach heparin reliably to the surfaces and not systemically heparinize the patient, or use less heparin. Of course during cardiopulmonary bypass it will reduce the blood loss. You will have less blood transfused; consequently, it will shorten the operating time. But the additional effect, which we do not know very much about, involves less complement activation and modifying immunologic response and having less anaphylactic reaction from the protamine, which can be a problem. Decreased stimulation from heparinized surfaces may decrease generation of free radicals, hemolysis, and the neutrophil activation. We have been using in the last 3% years both ionic fixation and end-point fixation of heparin in the tubing and the Maxima Medtronic oxygenator with the Carmeda. We have also had coated surfaces in the Bio-Medicus pump. We have performed a prospective, randomized study which was conducted by Dr Franz Agasa, who has done most of this experimental work and has been in charge of the clinical evaluation of this work. We used the Carmeda system in a prospective, randomized way for coronary revascularization. We used the same oxygenator in both groups, giving the group with the low heparinization 100 U/kg and the full heparinization 300 U k g . We maintained the activated clotting time during revascularization procedures of the low group greater than 180 seconds. We were not courageous enough to completely eliminate heparin. I think we will always need some heparin. In the other group the activated clotting time was
Ann Thorac Surg 1993;55:21M
kept about 480 seconds. We were able to grossly reduce, in a statistically significant way, the loss of blood and the amount of blood transfused. Half of the patients did not need any transfusions whatsoever. So the first clinical trial has shown that blood loss can be reduced and less blood is transfused. This was significant. We found no other significant differences. The second clinical trial used the Carmeda system devices on the roller pump and on the centrifugal pump for the resection of thoracic aortic aneurysms. Partial cardiopulmonary bypass has taken a lot of problems away when dealing with a big thoracic aneurysm, especially those extending below the diaphragm when you have to replace the whole aorta. This is our method of choice now. The only fatality that we had in this group was in a patient with a ruptured thoracic aneurysm, which are rather difficult to deal with as you all know. Of course there is a word of caution about using these heparincoated devices, because you can generate excessive thrombogenicity, and there is a theoretical danger of the closure of the bypass grafts, especially thrombosis of the endarterectomized artery and maybe a thrombus in the mechanical valve prosthesis. We have not observed that, but there is probably a need for a minimal heparinization. We found that thrombosis in the perfusion system may occur with minimal heparinization, and therefore special techniques have to be used to keep the blood moving constantly in the perfusion system. With this technique we have found no evidence of the activation of coagulation cascade.
MODERATOR COPELAND: Finally, Dr Cabrol will give us his vast experience from La Pitie Hospital. DR CABROL In our hospital we are not fortunate enough to have a hematology unit. So we had to engage a colleague, Dr Szefner, who specialized in this work, and this appears to be quite satisfactory. So the total experience is now 58 patients and more than 1,000 patient-days; 1 patient has had more than 600 days on the Jarvik. As our moderator explained, the anticoagulation must prevent many problems that are shared by many devices: fibrinolysis, exacerbation of platelet function, and exaggerated coagulation. We have to stop the fibrinolysis to stabilize the blood and the functions and to balance the coagulations. Fibrinolysis is due to the transformation of plasminogen to plasmin and destruction of fibrinogen and fibrin. To measure the fibrinolysis we have some test of plasminogen and fibrin degradation products. We treat fibrinolysis using aprotinin, one million units in intravenous injection followed by a drip of 4,000 U/min. The second problem is a strong and permanent activation of platelets. To measure this exaggerated platelet activation in vivo we use /3-thromboglobulin, platelet factor IV, and platelet aggregation in vitro. We normalize platelet function using dipyridamole in big doses, 600 to 1,200 mglday. When the platelet function is stabilized we use aspirin in very small doses, 50 to 100 mg a day. The third problem is to reestablish the normal balance between thrombin formation and neutralization by an-
CIRCULATORY SUPPORT PANEL II ANTICOAGULATION
215
tithrombin. To correct this excess of thrombin we use heparin, 1,000 to 5,000 U/day. I must that say we had no biological bleeding in that series. Of course we have some surgical but not biological; that was always controlled by the technique of our colleagues. Also we had only two thromboembolic events, both occurring in our patient who lived 600 days with the Jarvik. She had two small episodes of neurological troubles; they were very transient. Examination of the device after use showed absence of microscopic thrombi in high-risk sites like Dr Copeland said, especially around the valve, and absence of iatrogenic bleeding. Finally, the various alterations in platelet function and coagulation kinetics linked to total artificial heart implantation require permanent anticoagulation and antiaggregation as well as a suitable follow-up. The protocol must be able to explore all the systems involved to modulate treatments to individual needs.
MODERATOR COPELAND: We are open for questions. DR D. GLENN PENNINGTON (St. Louis, MO): I would like to ask Marko Turina a question. Let me give you a situation where you, let us say, have a Bio-Medicus pump and the Carmeda-coated tubing with Carmedacoated cannulas. You have that system ready and you put it in a patient for ventricular support. The question is as follows: How much anticoagulation would you think is necessary? Would you use none? Also, is it necessary to follow up antithrombin I11 levels? And if so, what are your limits? If the antithrombin 111 level falls below a certain level should we give heparin? What advice can you give us? DR TURINA: I do not think that you can eliminate the use of heparin altogether, because there are the vagaries of the implantation and there are times when you are not circulating in your system. There is always the danger of thrombosis. You are also running, especially if the patient has been receiving aprotinin, through some periods when the patient is in a hypercoagulable state. So to answer it simply in a situation like this, yes. We would use the heparinization that is used in vascular surgery just as the minimum heparinization to prevent some of the possible complications. We do not have hard data to prove that, but in the animal experiments when we had been running some of these devices they have been observed without any heparin whatsoever. We observed microemboli, and that is one of the pieces of indirect evidence that some heparin should be used. Only the activated clotting time is monitored. MODERATOR COPELAND: 1 would like to ask Dr Frazier a question. You said that bleeding seemed to be a problem. Is that bleeding device-related or is that related to technique? How would you go about minimizing the bleeding? DR FRAZIER Well, bleeding is a patient-related phenomenon. Actually, in the implantation of these devices
216
CIRCULATORY SUPPORT ANTICOAGULATION
PANEL I1
there is nothing intrinsically about their implantation that contributes a lot to bleeding. Obviously with the total artificial heart implantation there are long suture lines. With the left ventricular assist device, the Novacor and the Thermetics devices, the ventricular attachment is decompressed. There is no pressure. It is a low-pressure line and the aortic suture line is right in front of you. We use a woven graft and have never really had problems with the graft bleeding. So the bleeding that we have encountered has been from patients with advanced, longstanding heart failure or hepatic dysfunction; particularly more recently, patients on prolonged Inocor support with accompanying platelet dysfunction have just been a coagulation nightmare. And the bleeding is the problem, not clotting. MODERATOR COPELAND: So you treat the coagulopathy? DR FRAZIER I do. I wish we had access to aprotinin because it does seem that it might help with these difficult patients. MODERATOR COPELAND: Doctor McBride, you talked about pseudoneointima. How long had those grafts been implanted? Do you think that duration of implantation has something to do with the presence of pseudoneointima?
Ann Thorac Surg 1993;55:213&
DR McBRIDE: The longest patient had it implanted for more than a year, and he had this fine membrane that lined the graft and was densely adherent to the graft, which did not cause a problem with the function of the device at all. The other 2 patients, if I am not mistaken, had the device in for more than a month. DR MICHAEL ALIER (Houston, TX): I do not want to belabor a point, but what about heparin-induced thrombocytopenia in this whole group of patients who are intermittently on lots of heparin a long time? MODERATOR COPELAND: In our own experience that is one of the reasons we try to get off. In addition, we have had trouble keeping patients even on continuous heparin infusions because of oscillation of partial thromboplastin times. That is why we tend to move on to warfarin sodium fairly quickly. Dr Cabrol, have you had any trouble with that? You keep your patients continuously on heparin for the entire time that they have the device in place. Do you ever see falls in platelet counts or do you have trouble with using heparin? DR CABROL Well, no. So far we do not have any problems. We use heparin intravenously for some days, and after that we use subcutaneous heparin.