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Ann Thorac Surg 1998;65:S40-S44
© 1998 The Society of Thoracic Surgeons

Review of Efficacy Parameters

^a Hôpital Laënnec, Paris, France

Address reprint requests to Dr Pouard, Hôpital Laënnec, Assistance Publique-Hôpitaux de Paris, 42 rue de Sèvres, 75007 Paris, France

Presented at Risk Assessment of Major Perioperative Issues in Pediatric Cardiac Surgery, Washington, DC, May 7, 1997.

	Abstract

Top Abstract Introduction Trials of aprotinin in... Conclusion Discussion References

 
Background. The deleterious effects of cardiopulmonary bypass are greater in pediatric patients than in adults. The use of aprotinin to manipulate hemostasis has become an important factor in attempts to reduce adverse consequences of these effects.

Methods. This article reviews the literature on the use of aprotinin in pediatric cardiac surgery.

Results. Available studies have many deficiencies, often including lack of placebo control, nonhomogeneous populations and procedures, and absence of information on aprotinin plasma concentrations. Comparison of trial results is further complicated by differences in dose regimens, heparin-protamine protocols, and priming.

Conclusions. Further trials are required to adequately assess aprotinin effect on platelet preservation, particularly in neonates, to evaluate aprotinin’s antiinflammatory action, and to determine optimum dosages to achieve specific objectives. Aprotinin in pediatric cardiac surgery has been found to be associated with no adverse effects, to decrease fibrinolytic and probably platelet activation, and to offer important clinical benefits in specific groups of patients.

	Introduction

Top Abstract Introduction Trials of aprotinin in... Conclusion Discussion References

 
From the beginning of pediatric cardiac surgery, it has been recognized that the deleterious effects of cardiopulmonary bypass are greater in children and infants than in adult patients. Hemodilution and a marked host-defense mechanism are the main reasons for this exacerbated reaction, perhaps more than the patient’s immaturity per se. Hemodilution is the most important factor, because the pump prime may be two to four times greater than the patient’s estimated blood volume. The hemodilution that occurs in pediatric patients sometimes is fivefold to tenfold greater than in adult patients. This increases the risk of bleeding and capillary leakage; many of us who have long worked in pediatric cardiac surgery can remember puffy, swollen babies leaving the operating room at twice their prior weight. The end result may be organ dysfunction, manifesting first in the lungs with hypoxemia and edema and then progressing to myocardial edema, renal failure, and sometimes brain damage and seizure.

Deleterious consequences include homologous blood exposure, prolonged operating room time, and delayed sternal closure, with the delay possibly extending for days. Other adverse results include prolonged duration of mechanical ventilation and prolonged stay in the pediatric intensive care unit, morbidity and mortality, and increased hospital charges. Each potential consequence can be a parameter of efficacy.

Our first attempts to counter the deleterious effects of cardiopulmonary bypass in pediatric patients involved using prostaglandins to bring patients to the operating room in better condition. Then improvements in anesthetic agents reduced their hemodynamic effect. We now use myocardial preservation to reduce the need for inotropic support and decrease the duration of ventilation. We use nitric oxide to manage pulmonary hypertensive crisis. We attempt to control the host-defense mechanism with hemofiltration, which enables us to somewhat reduce bleeding, reduce the need for inotropic support, and increase the infant’s oxygen tension at the end of bypass. And now we are attempting to manipulate hemostasis, first with antifibrinolytic drugs such as tranexamic acid, vitamin K, and -aminocaproic acid, and since the reports of Bidstrup and associates [1], with aprotinin.

	Trials of aprotinin in pediatric cardiac surgery

Top Abstract Introduction Trials of aprotinin in... Conclusion Discussion References

 
Early trials conducted in the 1980s were open trials that often began administration of aprotinin before the procedure and administered aprotinin together with vitamin K and other fibrinolytics. So even when results showed reduced blood loss and decreased mediastinal bleeding [2, 3], the effect of aprotinin remained unclear.

A first pilot study, using historical control, was conducted in London at the Hospital for Sick Children in 1990 [4]. A high-dose regimen was administered to 28 patients selected for high risk of bleeding, which included those undergoing transposition of the great arteries or reoperation, or patients with endocarditis. Although no reduction in blood loss or drainage was observed, there were no adverse effects and chest closure time was significantly reduced.

In 1991, Mössinger [5] showed that aprotinin could attenuate the hemostatic change during cardiopulmonary bypass. In 1992, Müller and colleagues [6] reported that a high-dose aprotinin regimen in 100 children resulted in lower blood requirements intraoperatively and postoperatively than in a historical control. Diuresis was increased, with no impairment of renal function. However, the report provided no information about the priming solution or the statistical analysis.

Two apparently conflicting reports appeared in the same issue of The Journal of Thoracic and Cardiovascular Surgery in 1993 [7, 8]. In a study of hemostatic activation during cardiopulmonary bypass with high and low dosages of aprotinin, Dietrich and associates [7] found a dose-dependent reduction of fibrinolysis and reduced activation of coagulation, with aprotinin decreasing thrombin generation. This was the first report to show aprotinin as having an anticoagulant effect in clinical practice. It also was the first reported use of aprotinin during deep hypothermic circulatory arrest (DHCA), with no harmful effects observed. This report also is noteworthy in that the aprotinin dosage is cited in terms of plasma concentration; the absence of this information probably is the most glaring fault in all other reports of aprotinin pediatric use to date. In this randomized, placebo-controlled study of 60 pediatric patients of quite homogenous weight, aprotinin decreased blood loss and blood-bank exposure [7]. But Boldt and coworkers [8], also in a randomized, placebo-controlled study of 60 pediatric patients, found no effect of aprotinin on platelets, blood loss, and homologous blood-transfusion requirement. However, in this study 500 mL of priming was used for all patients, with patient weight varying between 5 kg and 15 kg, so that dilution differed from patient to patient. Comparison of study results is difficult when information on aprotinin plasma concentration is lacking.

In another randomized study, this time with an untreated control, Boldt and coworkers [9] again found no influence of aprotinin on platelets and no reduction in blood loss and homologous blood requirement with aprotinin. Patients in this study were better stratified; however, the greater stratification made for smaller groups and consequently made statistical analysis difficult. These researchers also reported finding that aprotinin reduced the level of thrombomodulin, suggesting that aprotinin may act on still another level of the cascade [10].

The first truly placebo-controlled study was reported by Herynkopf and associates [11] in 1994. In this double-blind Brazilian study, a low-dose aprotinin regimen reduced postoperative transfusion requirements and increased the number of patients who required no blood transfusion. However, the study population was very nonhomogeneous, with patients ranging from 1 month to 15 years old and with body weight ranging from 5 kg to 60 kg. Also, this report provided no information about priming volume.

In a study of 80 patients with a historical control group of 55 patients, Penkoske and colleagues [12] reported that a high-dose aprotinin regimen reduced closure time, chest drainage, and blood-unit exposure. But, again, the population was nonhomogeneous and the aprotinin plasma concentration cannot be ascertained. A more interesting study with a very homogeneous population and nice statistical analysis was reported by D’Errico and coworkers [13] in 1996. This was a randomized, placebo-controlled, double-blind trial that compared the effects of high and low aprotinin doses and placebo in selected patients undergoing reoperative open heart surgical procedures. Results showed that aprotinin reduced blood-transfusion requirements, decreased operating room time, shortened duration of hospitalization, and reduced hospital charges. Of interest is that this study, although initially designed to include 80 patients, was prematurely terminated after 61 patients because the reduction of blood transfusion with aprotinin was so significant. Also of interest is that the study considered the surgeons’ subjective assessment of the dryness of the surgical field—a factor that is quite important even if difficult to subject to statistical analysis.

In 1997, Davies and colleagues [14] reported a randomized, placebo-controlled, double-blind study in a well-stratified but small group of 42 patients. They found that high-dose aprotinin decreased fibrinolytic and platelet activation but had no influence on drainage, hemoglobin loss, or transfusion requirement. This study too considered clinicians’ assessment of the surgical field; given the apparent usefulness of this factor as a parameter of efficacy it might be well to consider devising some form of electronic mapping or other medium that could make it usable in statistical analysis.

In two very specialized studies, Jaquiss and associates [15] showed that aprotinin reduced perioperative hemorrhage during lung transplantation in pediatric patients with a high risk of bleeding and Tweddell and colleagues [16] found that aprotinin decreased thoracic drainage in single-ventricle palliation. The latter report, of a completely retrospective study and published only as an abstract, also found that aprotinin also improved arterial saturation and, in patients undergoing the Fontan operation, decreased the transpulmonary gradient. These two findings may reflect an aprotinin effect on the inflammatory reaction more than on hemostasis. The finding of decreased thoracic drainage is interesting because in single-ventricular palliation the drainage may involve both blood and inflammatory reactions; very rarely is the volume of drainage sufficient to provide enough hemoglobin to make possible their distinction.

In an experimental study with immature piglets, Aoki and coworkers [17] showed that with DHCA, high-dose aprotinin improved the recovery of cerebral energy and decreased the water content of all organs except the brain. In light of retrospective studies [18, 19] that suggested that aprotinin may have some deleterious effects in adults during DHCA, it should be noted that the literature on the pediatric experience, which encompasses considerable use of aprotinin in DHCA, shows no harmful consequences associated with aprotinin [4, 5, 7, 11–13]. At my center in Laennec, about 320 of the approximately 6,000 procedures using aprotinin that we have done in infants and children have involved DHCA, also with no evidence of harmful consequences.

In addition to its effect on hemostasis, aprotinin may also enable manipulation of the inflammatory reaction, which is exacerbated in children. In simulated bypass, in which, of course, endarterial action is absent, Wachtfogel and coworkers [20] demonstrated that high-dose aprotinin may completely inhibit kallikrein activation, partially inhibit neutrophil activation, and decrease platelet activation. In an animal model, Ali and associates [21] showed decreased leakage with aprotinin. Himmelfarb and colleagues [22] found that during renal dialysis aprotinin completely inhibited complement activation but not neutrophil activation. And recently Royston [23] suggested that all the serine protease inhibitors, aprotinin as well as others, could reduce both cellular and immune [22] inflammatory reactions.

In adult patients, Hill’s group [24, 25] showed that aprotinin decreased bronchial lavage fluid, neutrophil activation, and the level of interleukin-8 compared with placebo. Our group [26] has recently reported that a decrease in interleukin-8 level may improve clinical outcome, the arterial/alveolar gradient, and duration of ventilation in babies.

Seghaye and associates [27] have shown that low-dose aprotinin has little or no effect on the inflammatory reaction. This is not surprising in light of our knowledge that aprotinin decreases the inflammatory effect on kallikrein only when used in very high doses.

	Conclusion

Top Abstract Introduction Trials of aprotinin in... Conclusion Discussion References

 
Very few studies have been done of aprotinin use in pediatric patients. Among the 14 reported studies, only six were randomized and only three placebo-controlled. Studies have used different dose regimens, and the plasma concentrations of aprotinin are unknown. They have been done with very nonhomogeneous populations, with patient ages ranging from 3 days to 16 years. Procedures also have been nonhomogeneous: An arterial switch with a very long suture line cannot be compared with a tetralogy of Fallot or even an old cardiopulmonary connection, which sometimes has more drainage. Different heparin-protamine protocols have been used, so protamine dosage may differ between studies. Priming has differed among studies, with some using whole-blood priming, which may interfere with coagulation, and others using clear priming.

Further trials clearly are required, with more patients, homogeneous populations, known plasma concentrations, and well-defined other criteria. Studies are required to assess platelet preservation; whereas platelet activation almost surely occurs in vitro, whether or not it occurs in vivo is uncertain. Further studies are indicated to assess aprotinin effects specifically in neonates; the special difficulty of such studies is the need for a considerable quantity of blood to assess platelet activation. Studies are needed to further evaluate aprotinin’s antiinflammatory action, as are studies to determine the optimum dose regimens for specific objectives. A very high dose regimen probably is best for the manipulation of hemostasis and attenuation of the inflammatory syndrome, but this is not known for certain. Some recent research shows an aprotinin effect in organ preservation; here, too, optimum dosage needs to be determined.

Our pediatric experience to date has established that aprotinin use has no adverse effects, can decrease fibrinolytic activation and probably platelet activation, and has important clinical benefits in specific groups of patients: patients undergoing reoperation, arterial switch procedures, and heart and lung transplantation.

	Discussion

Top Abstract Introduction Trials of aprotinin in... Conclusion Discussion References

 
QUESTION FROM THE AUDIENCE: In designing a prospective pediatric study, is it preferable to use age or body weight as the criterion for stratification?

DR POUARD: Actually, both age and body weight are important. Many teams have only two or three different priming volumes. If you use the same priming volume for a 3-kg and a 7-kg baby and you add aprotinin in relation to the patient’s weight, you do not have the same dilution. When you try to calculate the aprotinin plasma concentration in some reported studies, you find that some of the babies received not just a low dose but rather a homeopathic dose of aprotinin.

QUESTION FROM THE AUDIENCE: You alluded to the possible usefulness of aprotinin in decreasing end-organ injury. In the cost-containment environment that we now operate in, the duration of mechanical ventilation is a recurrent theme in considerations of high intensive care unit costs. Aprotinin’s effect on pulmonary function is probably also an area that we should at least consider in terms of trying to decrease overall costs of heart operations.

DR POUARD: The enhancement of organ function with aprotinin is a new area of exploration. You will recall that Dr David Royston began to study the effect of aprotinin on pulmonary membrane function. There are reports of both animal experiments and an adult trial showing that aprotinin improves myocardial function after clamping. And there is one widely known report that shows a lower troponin release when aprotinin is used.

But I think it is not yet time to talk about efficacy parameters for organ preservation with aprotinin. It is more urgent to find a way to compare the type of studies we are now doing to establish aprotinin efficacy, with trials that have good stratification in age and type of operation, and with specification of the priming volume as a quantity, how the priming is done, and whether the prime is clear, plasma, or whole blood. We absolutely need to know all this to establish aprotinin efficacy.

QUESTION FROM THE AUDIENCE: We have seen an increased tendency for clotting in Fontan patients when we use tranexamic acid. These patients present a very different type of situation, with a low-velocity flow through areas that have just been operated on, and there are artificial pathways for the blood to go through. Has any tendency toward thrombosis in the Fontan pathway been noted with aprotinin?

DR POUARD: We are just now studying this problem, because recently we had two superior vena cava thromboses on the catheter in a Fontan procedure. But like everyone in pediatric cardiac surgery, we have seen that thrombosis can be caused by many factors, including low arterial pressure, perhaps low flow, and increased hematocrit. So it is quite difficult to isolate any possible contribution of aprotinin. And in studying this problem, we have to find a suitable balance, because in a third or fourth reoperation we may have a positive effect of aprotinin for the end of bypass and a deleterious effect hours later in the intensive care unit.

We find our recent experience very strange, because we have been using aprotinin for 10 years now at our center and we have had no thromboses for years and years. Consequently, we think that it is not aprotinin but the combination of aprotinin and some coagulation fraction that may be involved. In France, we no longer are allowed to give whole blood and obtaining fresh plasma is quite difficult, so sometimes we give concentrates. At this stage of our study, we think that it is probably the concurrent administration of aprotinin and some coagulation fraction that is responsible for the thrombosis, but we do not know yet.

QUESTION FROM THE AUDIENCE: I find it interesting that Dr Bruce Miller at Emory, using routine heparinization practices, found that heparin levels fall to about 1 unit per milliliter, which is an incredibly low heparin concentration. So clearly there is no correlation between the prolongation of activated clotting time and heparin concentration.

I also would like to raise the issue of antithrombin levels. Even in adults, antithrombin levels fall to 30% to 40% during bypass. I feel that these phenomenally low levels, especially in conjunction with low heparin concentrations, may be responsible for some of the hyperthrombotic effects seen with or without aprotinin or any fibrinolytic inhibitor.

So I have a number of questions. What is the importance of the heparin-protamine interaction with aprotinin? And should we give more consideration to the role of antithrombin, especially in pediatric patients in whom there are such phenomenal dilutional changes? Also, Dr George Despotis has elegantly shown that more heparin and less protamine importantly inhibits thrombin generation activity. So what ratios of heparin and protamine should we be using in pediatric patients?

DR POUARD: At our center, we currently are focusing on antithrombin III, because we have noted some very low levels after bypass in small babies. Certainly a very low plasma concentration of antithrombin III facilitates thrombosis. Without sufficient antithrombin III, it makes no difference what the heparin level is because any heparin present is inactive. So it is of major importance whenever heparin is given or the regimen of heparin is changed to be sure that the right level of antithrombin III is present.

I do not know what importance the protamine-heparin interaction has in relation to aprotinin. In our practice, we give a loading dose and then continuous infusion of heparin during bypass. Then when we have to reverse with protamine, we give the quite low dose of 0.8 mg per milligram of heparin. In the reported trials that I have referred to, the protamine levels given for reversal have varied between 0.8 mg and 1.6 mg.

DR WULF DIETRICH (Munich, Germany): Permit me to contribute a comment. We know that in pediatric patients the balance between coagulation and fibrinolysis is the same as in adults, but on a lower level. So the lower antithrombin level corresponds to a lower level on the other side of the balance. But in cyanotic patients, patients who undergo the Fontan procedure or other procedures, the balance is more toward the fibrinolytic system, and these patients are hyperfibrinolytic. In these patients, if you inhibit this part of the hemostatic cascade with pure antifibrinolytics, you may tilt their balance toward the coagulation side of the cascade and cause a hypercoagulate state.

This may be the advantage offered by aprotinin, because aprotinin acts on both sides of the hemostatic cascade. At high enough levels, it inhibits thrombin and it also inhibits fibrinolysis.

However, I believe that thrombosis after Fontan or Glenn procedures is mainly a result of the venous upflow and not hemostatic disturbances. So we use aprotinin in all our Fontan procedures. Of course, like everyone, we have seen some thrombotic events in our patients, but these were caused by surgical mismanagement or decreased lung perfusion.

	References

Top Abstract Introduction Trials of aprotinin in... Conclusion Discussion References

 

1. Bidstrup B.P., Royston D., Sapsford R.N., Taylor K.M. Reduction in blood loss and blood use after cardiopulmonary bypass with high dose aprotinin (Trasylol). J Thorac Cardiovasc Surg 1989;97:364-372.[Abstract]
2. Popov-Cenic S., Urban A.E., Noe G. Studies on the cause of bleeding during and after surgery with heart-lung machine in children with cyanotic and acyanotic congenital cardiac defects and their prophylactic treatment. In: McConn R., ed. Role of chemical mediators in the pathophysiology of acute illness and injury. New York: Raven Press, 1982:229-242.
3. Urban A.E., Popov-Cenic S., Noe G., Kulzer R. Aprotinin in open-heart surgery of infants and children using the heart-lung machine. Clin Ther 1984;6:425-433.[Medline]
4. Elliott M., Allen A. Aprotinin in pediatric cardiac surgery. Perfusion 1990;5:73-76.
5. Mössinger H., Dietrich W., Spannagel M., Henze R., Barankay A., Richter J.A. High-dose aprotinin reduces not only fibrinolytic, but also clotting activation in pediatric cardiac surgery. Fifteenth Annual Meeting of the Society of Cardiovascular Anesthesiologists, San Diego, CA, April 24–28 1993;249.
6. Müller H., Alken A., Ziemer G., et al. Aprotinin in pediatric cardiopulmonary bypass surgery. Cardiothorac Vasc Anesth 1992;6(Suppl 1):100.
7. Dietrich W., Mössinger H.J., Spannagl M., et al. Hemostatic activation during cardiopulmonary bypass with different aprotinin dosages in pediatric patients having cardiac operations. J Thorac Cardiovasc Surg 1993;105:712-720.[Abstract]
8. Boldt J., Knothe C., Zickmann B., Wege N., Dapper F., Hempelmann G. Comparison of two aprotinin dosage regimens in pediatric patients having cardiac operations: Influence on platelet function and blood loss. J Thorac Cardiovasc Surg 1993;105:705-711.[Abstract]
9. Boldt J., Knothe C., Zickmann B., Wege N., Dapper F., Hempelmann G. Aprotinin in pediatric cardiac operations: platelet function, blood loss, and use of homologous blood. Ann Thorac Surg 1993;55:1460-1466.[Abstract]
10. Boldt J., Zickmann B., Schindler E., Welters A., Dapper F., Hempelmann G. Influence of aprotinin on the thrombomodulin/protein C system in pediatric cardiac operations. J Thorac Cardiovasc Surg 1994;107:1215-1221.[Abstract/Free Full Text]
11. Herynkopf F., Lucchese F., Pereira E., Kalil R., Prates P., Nesralla I.A. Aprotinin in children undergoing correction of congenital heart defects: A double-blind pilot study. J Thorac Cardiovasc Surg 1994;108:517-521.[Abstract/Free Full Text]
12. Penkoske P.A., Entwistle L.M., Marchak B.E., et al. Aprotinin in children undergoing repair of congenital heart defects. Ann Thorac Surg 1995;60:S529-S532.
13. D’Errico C., Shayevitz J.R., Martindale S.J., Mosca R., Bove E.L. The efficacy and cost of aprotinin in children undergoing reoperative open heart surgery. Anesth Analg 1996;83:1193-1199.[Abstract]
14. Davies M.J., Allen A., Kort H., et al. Prospective, randomized, double-blind study of high-dose aprotinin in pediatric cardiac operations. Ann Thorac Surg 1997;63:497-503.[Abstract/Free Full Text]
15. Jaquiss R.D., Huddleston C.B., Spray T.L. Use of aprotinin in pediatric lung transplantation. J Heart Lung Transplant 1995;14:302-307.[Medline]
16. Tweddell J.S., Berger S., Frommelt P.C., et al. Aprotinin improves outcome of single-ventricle palliation. Ann Thorac Surg 1996;62:1329-1335.[Abstract/Free Full Text]
17. Aoki M., Jonas R.A., Nomura F., et al. Effects of aprotinin on acute recovery of cerebral metabolism in piglets after hypothermic circulatory arrest. Ann Thorac Surg 1994;58:146-153.[Abstract]
18. Sundt T.D., Kouchoukos N.T., Saffitz J.E., Murphy S.F., Wareing T.H., Stahl D.J. Renal dysfunction and intravascular coagulation with aprotinin and hypothermic circulatory arrest. Ann Thorac Surg 1993;55:1418-1424.[Abstract]
19. Westaby S., Forni A., Dunning J., et al. Aprotinin and bleeding in profoundly hypothermic perfusion. Eur J Cardiothorac Surg 1994;8:82-86.[Abstract]
20. Wachtfogel Y.T., Kucich U., Hack C.E., et al. Aprotinin inhibits the contact, neutrophil, and platelet activation systems during simulated extracorporeal perfusion. J Thorac Cardiovasc Surg 1993;106:1-9.[Abstract]
21. Ali M., Becket J., Brannan J., Fleming J., Taylor K.M. The effect of high dose aprotinin therapy on the systemic inflammatory response in a porcine model of cardiopulmonary bypass. Perfusion 1996;11:278-280.[Free Full Text]
22. Himmelfarb J., Holbrook D., McMonagle E. Effects of aprotinin on complement and granulocyte activation during ex vivo hemodialysis. Am J Kidney Dis 1994;24:901-906.[Medline]
23. Royston D. Serine protease inhibition prevents both cellular and humoral responses to cardiopulmonary bypass. J Cardiovasc Pharmacol 1996;27(Suppl 1):S42-S49.
24. Hill G.E., Alonso A., Spurzem J.R., Stammers A.H., Robbins R.A. Aprotinin and methylprednisolone equally blunt cardiopulmonary bypass-induced inflammation in humans. J Thorac Cardiovasc Surg 1995;110:1658-1662.[Abstract/Free Full Text]
25. Hill G.E., Pohorecki R., Alonso A., Rennard S.I., Robbins R.A. Aprotinin reduces interleukin-8 production and lung neutrophil accumulation after cardiopulmonary bypass. Anesth Analg 1996;83:696-700.[Abstract]
26. Journois D., Isreal-Biet D., Pouard P., et al. High-volume, zero-balanced hemofiltration to reduce delayed inflammatory response to cardiopulmonary bypass in children. Anesthesiology 1996;85:965-976.[Medline]
27. Seghaye M.C., Duchateau J., Grabitz R.G., et al. Influence of low-dose aprotinin on the inflammatory reaction due to cardiopulmonary bypass in children. Ann Thorac Surg 1996;61:1205-1211.[Abstract/Free Full Text]

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pouard, P. Search for Related Content PubMed PubMed Citation Articles by Pouard, P.