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Ann Thorac Surg 1998;65:S74-S76
© 1998 The Society of Thoracic Surgeons
Address reprint requests to Dr Greeley, Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia, 34th St and Civic Center Blvd, Philadelphia, PA 19104-4399
Presented at Risk Assessment of Major Perioperative Issues in Pediatric Cardiac Surgery, Washington, DC, May 7, 1997.
DR WILLIAM J. GREELEY (Philadelphia, PA): Based on all of the information presented at this symposium, we need to obtain a consensus regarding the use of aprotinin in pediatrics, and see if there are common agreements on some of the issues discussed and on what other issues need further strategic, selective focus. Let me start with the uses or indications for aprotinin in pediatric patients. Is there any commonality?
DR ERIC L. CEITHAML (Jacksonville, FL): We all recognize that redo surgery is one important area, but I think that patient selection is going to be a very important issue. A multicenter trial would need to get enough patients to make some worthwhile statements. I think, personally, transposition of the great vessels and the operative procedure of arterial switch would be issues that we would want to consider.
DR GREELEY: Let me be the devil’s advocate and ask whether you have heard enough today on aprotinin’s use for redos to form a consensus that this should be an indication. And if so, is it necessary to restudy this area? Or do you feel that the information presented today is not sufficient?
DR WULF DIETRICH (Munich, Germany): I think that first we should consider what is the end point. What are our expectations for the use of aprotinin? Are we looking for a reduced bleeding tendency or reduced allogeneic blood requirement? If this is the case, then redo patients and children in higher age ranges are the best patients. If we are interested in getting at the mode of action of aprotinin by means of measuring inflammatory and coagulation parameters, then we need a homogeneous patient group. Take, for example, the transposition group. These are very small babies and are homogeneous patients. But I would not expect any difference in bleeding tendency in these patients, and I am sure that there is no difference in homologous blood requirement. So it depends on what is the primary end point of a study. I would suggest, because I am more interested in the mode of action, that hemostatic parameters are the end point studied.
DR GREELEY: Before we get to that, let’s discuss safety and efficacy. First, is the drug safe for use in children? Are there safety issues still to be resolved?
DR DIETRICH: Well, for us, this problem is solved. We have used aprotinin 6,000 times, and the people from France have used it a similar amount, and there are no attributable problems besides anaphylactic reactions to this drug. We have the opposite problem in convincing our surgeons to operate on patients without aprotinin.
DR GREELEY: OK. So nobody disagrees, in general, that the experiences presented here today from a variety of institutions on both sides of the Atlantic would suggest that it is a safe drug to be used.
QUESTION FROM THE AUDIENCE: There is one area I have always been worried about: If aprotinin is going to be used to reduce bleeding, is it children in whom you end up doing a low-flow procedure, like a Glenn shunt, or Fontan, and situations where patients are given warfarin afterwards. I am worried about thrombosis in these patients, especially in light of a recent article in The Annals of Thoracic Surgery about the high incidence of thrombosis in central venous lines in a pediatric population. Unfortunately, I did not see the data presented this morning from Europe. Were there any data presented on this?
DR CELIA C. D’ERRICO (Ann Arbor, MI): There were just experimental, anecdotal data. Actually, a concern was raised by Paul Hickey about that. The sense of the group this morning was that some groups with vast experience have not seen this problem, and others have. I certainly think that the diagnostic patient group you refer to certainly would merit further investigation.
DR PAUL R. HICKEY (Boston, MA): Doctor D’Errico, you may want to address this from the perspective of the University of Michigan experience.
DR D’ERRICO: Basically, we are using aprotinin in all our Fontan procedures without any coagulation-related problems. Our published study was probably more than a third Fontan operations, and when we looked long-term at our chest-tube drainage, it was all fairly equal.
DR HICKEY: May I respond to that? With tranexamic acid, we saw premature closure of the fenestration in several patients with Fontan procedures who got into some hemodynamic trouble subsequently. This raises an issue that I think is in some way key to aprotinin’s role in pediatric cardiac surgery patients, and that is, are its properties, other than antifibrinolysis, unique and more than what one gets with tranexamic acid or aminocaproic acid? In terms of justifying its cost in comparison with the other antifibrinolytics, this is where the issue really becomes very critical and central to the decision of whether or not to go with aprotinin. If it does provide a better balance and less tendency toward thrombosis than these other compounds and its antiinflammatory actions are shown to be important, this may result in improved outcome with reduced intensive care unit stay, fewer days on the ventilator, and better lung compliance. I think this will make a very good rationale for going with aprotinin despite its cost, because it has more than the antifibrinolytic action of aminocaproic acid or tranexamic acid.
DR JAMES S. TWEDDELL (Milwaukee, WI): I just wanted to add our experience with aprotinin concerning the single ventricle question. We compared, in a contemporary series, patients who received aprotinin and those who did not who underwent bidirectional Glenn and Fontan procedures. We found a significantly favorable impact of aprotinin in bidirectional Glenn procedures: shorter duration of chest-tube drainage, lower transpulmonary gradient, and higher oxygen saturation. So I think that may reflect the antiinflammatory properties. I also would agree that perhaps the use of aprotinin in some of the neonatal operations, particularly transposition, might be something worth looking at. I do not think there is anybody here from Great Ormond Street, but I understand that they are using it now in transposition.
DR ROSS M. UNGERLEIDER (Durham, NC): Doctor Tweddell, do you think the outcome parameters should be inflammatory ones or bleeding ones?
DR TWEDDELL: I think the antiinflammatory impact of aprotinin is something that really needs to be looked at carefully.
DR PHILIPPE POUARD (Paris, France): I have just a comment. Before talking about manipulating hemostasis, I think we have to take into account differing blood transfusion practices. Completely different hemostatic responses can be seen with fresh whole blood compared with an old separated unit. For example, in France, it is now impossible to use fresh whole blood. So we definitely need some manipulation of hemostasis. But for people who have fresh blood available, it is completely different. In most of the cases, I think you can completely avoid the use of any drugs when you have good, fresh whole blood.
DR UNGERLEIDER: I am curious. Is there anybody in this audience who is able to get fresh whole blood for use in patients? That is 4 of about 30 of you.
QUESTION FROM THE AUDIENCE: We have fresh donor blood, from families.
DR UNGERLEIDER: Is that donated fresh on the day of the operation?
QUESTION FROM THE AUDIENCE: Within 24 to 48 hours.
DR D’ERRICO: Our blood bank is able to have blood available for 7:00 AM if the family donates it up until 5:15 the night before. So in some patients we do have that. In addition to that, the blood bank is able to get us, nine times out of ten, 24- to 48-hour-old blood for the pediatric cases.
QUESTION FROM THE AUDIENCE: We get fresh whole blood, donated the evening before the operation, that is tested at 6 AM the following morning. We have fresh whole blood in about 90% to 95% of our cases, and this unit of fresh whole blood together with the pump prime is usually sufficient. These differences in blood-transfusion practice highlight some of the problems with any study design. In addition, the use of ultrafiltration and white cell filters varies between patients and institutions and will further complicate the design of a multicenter, randomized study.
DR AARON HILL: Another suggestion in terms of study design is to be aware of the varying techniques of anesthetic management between and within institutions, as well as the use of other antiinflammatory agents. There is no uniform use of steroids, for example, with bypass in the pediatric population. Also, with the new emphasis on fast-tracking, the anesthetic management is changing very rapidly to try to aim for early extubation, for example.
DR GREELEY: I understand the problems, but having come from an institution where we did a 40-site, 31-country clinical study of 40,000 patients in 18 months, I know it can be done. It is just a matter of design. Also, obviously it depends on the resources and the need for the information.
DR D’ERRICO: I want to comment on that. A lot of the studies will tell you that a good surgeon will take care of all your blood loss. However, it is always possible to improve results, even with a phenomenal surgeon. There are still a lot of things we can change, not necessarily just the fact that you are going to use less blood. The antiinflammatory properties of aprotinin may be important here. Doctor Hickey is doing a wonderful job looking at long-term outcomes. I know that parents whose child undergoes bypass are more concerned about how well their child is when taken home than whether or not one unit or three units of blood were used.
DR GREELEY: How about dose? I saw today many different dosing schemes. Is there one set dose that we can recommend? Is the limitation about dosing a pharmacokinetic and pharmacodynamic issue?
DR POUARD: I think we have to be logical. The drug appears to be safe, so why not use the highest dose, ie, the high-dose regimen, to have the maximum effect?
DR GREELEY: What is that high dose, then? Can it be higher?
DR POUARD: Yes, possibly.
DR DIETRICH: What we have learned from our studies is that the higher the dose, the greater the effect on the coagulation pathway; in other words, the better the thrombin-inhibiting effect of aprotinin. This is a unique action of aprotinin; with lower doses, we do not get this effect and only have a sole antifibrinolytic effect, as occurs with tranexamic acid or 
-aminocaproic acid. So we should go to a high dosage.
DR GREELEY: So the first step, then, is to set up a study to obtain a dose-response curve. It has been done in selected institutions in different ways, but now it needs to be studied more systematically.
DR POUARD: I think we absolutely have to do that, because if we do not know the plasma level of the drug, we will be unable to adapt the dose to the total blood volume of the patient and the pump-prime volume. I would like to hear Dr Boldt’s opinion, as I think you believe that the plasma level is not very important.
DR JOACHIM BOLDT (Ludwigshafen, Germany): During anesthesia we measure plasma levels of everything: opiates, heparin, and anesthetics. Midazolam and benzodiazepine plasma levels are unrelated to efficacy. Why do we measure heparin plasma levels? We know that there is no good correlation between plasma levels and efficacy. Is it really important what plasma level we achieve with aprotinin? We have tremendous results with very low doses of aprotinin. We have tremendous results even giving it topically in the open heart, in the open chest. There are many conflicting results concerning the different doses given. I think, at this point, it is not true to say the highest dose is the best dose. And we have to think a little bit about cost as well.
DR GREELEY: So what would you suggest?
DR BOLDT: We have to do dose-response studies, looking at different end points, not only a target like blood loss but also coagulation parameters and inflammatory parameters.
DR JERROLD H. LEVY (Atlanta, GA): Can I just make a quick comment? It may not be necessary to do a dose-response study. A pharmacokineticist should be able to calculate the dose based on the data available in adults and the patient’s weight and the size of the bypass reservoir.
DR GREELEY: OK, so we cannot come to a consensus on dose. How about contraindications? Are there any specific patients in whom it absolutely should not be used? Do you consider an elevated creatinine level a contraindication to the use of aprotinin? Does anybody want to comment on that?
DR ROBERT F. CONIFF (West Haven, CT): I might just comment on that. John Lemmer from Portland, Oregon, published last year his experience in using aprotinin in adult patients undergoing chronic hemodialysis with end-stage renal disease. His experience in this series of patients from his own group’s practice was very good. They had good results, and there were no obvious safety issues in these patients with advanced renal disease.
In addition, we recently reevaluated changes from baseline in creatinine levels, looking at different levels of clinical importance. Although initially there was one study done in the United States in valve patients that showed an increased incidence of renal problems, our coronary artery bypass graft studies did not confirm this. Pooled data from all of our large, placebo-controlled, multicenter trials showed that there really was no issue.
DR LEVY: The valve study was a multicenter study that I was involved in. The interesting thing, just to add to Dr Coniff’s point, is that although creatinine levels did rise, they all returned back to baseline. One of the other problems with this study, in retrospect, was that the patients were small (40 to 50 kg) individuals getting full-dose aprotinin for extended periods of time. Aprotinin is taken up by the proximal tubule and will produce a potassium-sparing diuresis. So if you use a lot of it, you may have a great diuresis, but be very careful about potassium replacement, because it causes only transient tubular dysfunction. It is always reversible, as in this study.
DR GREELEY: Let me ask you, Dr Levy: What do you do in your patients who have a preoperative elevated creatinine level and an otherwise-indicated need for aprotinin?
DR LEVY: We give aprotinin for all these patients, from the anuric dialysis patient, where there really is a great risk-benefit ratio, to the other patients.
DR GABRIELLE HECKER (Wuppertal, Germany): If we are going to design a study looking at inflammatory parameters, which ones would be recommended that would really translate into clinical benefits? So far I have only seen reduction in interleukins or tumor necrosis factor. Which ones would you recommend to give an idea about improved clinical outcome?
DR GREELEY: Are there any suggestions? We have heard that chest-tube drainage does not make a difference; blood loss does not seem to make a difference. How about what Dr D’Errico presented today? Any future study is going to have to include cost-effectiveness. There is just no doubt in my mind that you are going to have to show that it adds value compared with the alternative or existing therapy, either in terms of same outcome/reduced cost or better outcome. The cost-effectiveness has to be more than just the cost of the drug, it has to be how it affects such things as length of time in the intensive care unit, length of mechanical ventilation, and length of hospital stay.
DR DIETRICH: Defining a clinically significant outcome parameter still remains a difficult issue. On the other hand, pharmacologic outcome parameters—for example, less thrombin generation or less interleukin-6, interleukin-8, or interleukin-10 production—are more commonly used end points. However, whether these will translate into a clinical benefit is another question. So I think we should decide whether we want to have a clinical outcome parameter or whether we want to have an outcome parameter that defines less inflammatory or hemostatic activation.
DR GREELEY: OK, what you are saying is, you want to look at primary and secondary outcome measures. The secondary ones all suffer from being surrogate. One of the most accepted primary outcomes is all-cause mortality, but you need big numbers for that, which is always a problem, particularly in this patient population.
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