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Thrombosis in children with BT shunts, Glenns and Fontans
Progress in Pediatric Cardiology 21 (2005) 17 – 21 www.elsevier.com/locate/ppedcard
Thrombosis in children with BT shunts, Glenns and Fontans Paul Monagle * Department of Haematology, Royal Children’s Hospital Chair, Head of Department of Pathology, University of Melbourne, Flemington Rd. Melbourne, Victoria 3052, Australia Available online 22 November 2005
Abstract Children with congenital heart disease (CHD) constitute a major proportion of children seen in tertiary hospitals with thromboembolic disease (TE). Three common surgical procedures are the Blalock – Taussig (BT) shunt, Glenn shunt and the Fontan surgery. All of these procedures can result in TE. There are few well designed studies in the literature determining the epidemiology of TE in these cohorts, however, TE has been diagnosed in children, especially following the BT shunt and the Fontan surgery. The best approach to treat or prevent TE complications in these cohorts of children has not been determined. Clinical studies are urgently required to provide evidence based recommendations for treatment and prophylaxis of TE. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Pediatrics; Congenital heart disease; Blalock – Taussig shunts; Glenn shunts; Fontan procedure; Thrombosis
Congenital heart disease (CHD), with a wide spectrum of severity, affects approximately 1% of all live births. The majority of congenital cardiac structural abnormalities occur in otherwise healthy children and total correction of the cardiac lesion usually results in a normal productive lifespan. Thromboembolic disease (TE) has been termed the new epidemic of pediatric tertiary care hospitals. Nowhere is this more evident than in cardiac and cardiac surgical children. Improved survival for these children over the last decade has been the result of tremendous advances in surgical techniques, availability of new drugs and new applications for old drugs, and developments in critical and supportive care. Despite this, one of the most frequent complications seen in survivors of CHD is TE, which include venous, arterial and intracardiac TEs, pulmonary embolism, and embolism to the central nervous system. Venous TEs in children with CHD have a mortality of approximately 7%. Morbidity in the form of post phlebitic syndrome and recurrent venous TEs occurred in 23% of children. Children with CHD constitute a major proportion of children seen in tertiary hospitals with TE. Recent data show that almost 50% of infants less than 6 months, and 30% of * Tel.: +61 3 93455919; fax: +61 3 93491819. E-mail address: [email protected]. 1058-9813/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ppedcard.2005.09.003
older children who suffer venous TE have underlying cardiac disorders. Similarly, almost 70% of infants (< 6 months) and 30% children who suffer arterial TE have underlying cardiac defects. In addition, the majority of children on primary anticoagulant prophylaxis are being treated for complex CHD or severe acquired cardiac illness. Three common cardiac surgical procedures are Blalock– Taussig (BT) shunts, Glenn procedures, and Fontan surgery. In many patients these surgeries will be performed sequentially. The initial BT shunt during the neonatal period, followed by a Glenn procedure as the first stage towards a final Fontan procedure which is the definitive palliative surgery. Thrombosis can occur as a complication of each procedure, however the implications of thrombosis differ for each surgical procedure, as does the management and potential outcome. There remains little conclusive evidence to support the optimal treatment strategies for thrombotic complications of these procedures. This paper will discuss thrombosis as a complication of each of these surgical procedures.
1. Blalock –Taussig (BT) shunt BT shunts are commonly performed in the neonatal period to increase pulmonary blood flow. BT shunts may be
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P. Monagle / Progress in Pediatric Cardiology 21 (2005) 17 – 21
performed as a single palliative procedure with planned later more definitive surgery, or as part of a more complex surgical intervention (e.g. Norwood procedure). In classic BT shunts, the subclavian artery is anastomosed directly to the ipsilateral pulmonary artery. The procedure is usually performed on right side, unless there is a right sided aortic arch, in which case the shunt is performed on the left. In contrast, for a modified BT shunt a Gore-tex tube graft is placed between the subclavian artery and the ipsilateral pulmonary artery. The Gore-tex tube may be as small as 3 mm diameter, depending on the size of the infant, but is usually 3.5 or 4 mm in diameter. The natural history of BT shunts has been assessed using angiography. Godart et al. assessed BT shunt growth and development of stenosis and distortion in 78 patients at a mean follow up time of 51 months [1]. They found that growth of the pulmonary arteries occurred but did not exceed the normal growth of the pulmonary arterial tree. However, a shunt procedure could cause distortion and stenosis of the pulmonary artery which may have important implications for future corrective surgical intervention. Patients with BT shunts may have reduced peripheral pulses in the ipsilateral arm, and may have measurably reduced growth of the arm. This can be of significance when assessing for post thrombotic syndrome which may occur in the upper limbs secondary to central venous thrombosis (see Fig. 1). Blockage of the BT shunt will compromise pulmonary blood flow and is often a major clinical event requiring immediate surgery. The incidence of thrombotic occlusion of BT shunts in the literature ranges from 1 to 17% [2– 16]. Risk factors for patency and stenosis include the age of the patient and graft size [2,3]. Diagnosis is usually
Fig. 1. Teenage boy with previous BT shunt on the right side, and venous thrombosis in the left brachial/axillary vein. Note the difference in size of the arms. There was noticeable reduced hair growth on the right arm. The boy was left handed.
clinical, although echocardiography, and angiography can be of value. There is no consistent approach to the prevention of thrombosis of BT shunts. Many investigators use antithrombotic therapy beginning with therapeutic doses of heparin and followed by low dose aspirin (1 to 10 mg/kg/ day) [15], although others recommend intraoperative heparin with no further anticoagulation [16]. There is no data from randomized trials to demonstrate clinical superiority of either approach. Children who develop acute BT shunt occlusion usually require some form of intervention which include thrombolytic therapy and/or stenting. Local thrombolytic therapy with tissue plasminogen activator and streptokinase have been used successfully in some children [9,17]. Angioplasty, balloon dilation, stent implantation [6,18] and repeat surgery [2,4] are other therapeutic options. The latter usually require subsequent anticoagulation therapy.
2. Glenn procedure (BCPS) The bidirectional cavopulmonary shunt(BCPS) or bidirectional Glenn procedure is an end (superior vena cava) to side (right pulmonary artery) venous shunt. This is a palliative procedure that increases oxygen saturation, but without increasing left ventricular work, and is usually performed in children with univentricular cardiac physiology, as the first stage of the two stage Fontan procedure. The IVC is unchanged after a Glenn procedure. The implications with respect to thrombosis are that, following a Glenn procedure, the SVC blood flows directly to the lungs without any assistance from the heart. Hence any reduction in SVC flow, due to thrombus occlusion, will dramatically reduce pulmonary blood flow. Pulmonary emboli are of specific concern in that if the pulmonary vascular resistance is increased, the patient may become unsuitable for a Fontan completion, which limits long term survival significantly in the absence of cardiac transplantation. Blood flow from the IVC still bypasses the lungs, meaning that any thrombus in the lower venous system can give rise to paradoxical emboli. Collaterals around central venous thrombosis may interfere with the ability to complete the Fontan surgery. The threat of being unable to complete the Fontan may be a justification for more aggressive antithrombotic therapy (thrombolysis or surgery) than might otherwise be indicated. Thrombotic complications following the Glenn shunt are infrequently reported [19 – 21]. There appears to be no data to support the need for routine thromboprophylaxis. However, once again, the fact that many patients subsequently proceed to Fontan procedures has led to some suggestions that thromboprophylaxis is warranted after a Glenn shunt to reduce the risk of thrombosis in the pulmonary vasculature, hence increasing the likelihood of successful conversion to a full Fontan circuit. Current clinical practices vary, and
P. Monagle / Progress in Pediatric Cardiology 21 (2005) 17 – 21
include: no anticoagulation, heparin followed by aspirin, heparin followed by warfarin therapy. There is no evidence to support a preference for any of these approaches at this time.
3. Fontan procedure There are numerous modifications of the Fontan procedure, but the basic principles remain the same. Both the SVC (usually done in a first stage BCPS) and the IVC are anastomosed to the pulmonary arteries. Hence the pulmonary blood flow is totally passive, depending on venous flow mechanisms without any cardiac pump assistance. The univentricle is then able to function as a left ventricle, providing systemic blood flow. Post operatively, many patients have deliberate, limited, right to left interatrial shunting via a ‘‘fenestration’’. The blood flow in such cases increases the risk of paradoxical emboli. The implications with respect to thrombosis following Fontan surgery are significant. First, the presence of right to left communication continues the potential for paradoxical emboli. Second, any pulmonary emboli which increase pulmonary vascular resistance have an accentuated impact on pulmonary blood flow, as the pulmonary pressure cannot be increased to overcome a pressure gradient. The Fontan circuit makes the diagnosis of pulmonary emboli particularly difficult. Depending on the attachment of the SVC and IVC to the pulmonary arteries, isotope may need to be injected into both an arm and a leg to achieve full lung perfusion scanning. As for patients with severe pulmonary hypertension having ventilation/perfusion scans, the transient obstruction of pulmonary capillaries by the macro-aggregated isotope labeled albumin may rarely precipitate a hypoxic episode. Finally, depending on the exact type of Fontan surgery, the risk of late (many years later) thrombosis associated with dysrythmias may be increased. The incidence of thrombosis after Fontan surgery has not been determined by prospective trials. Three cross sectional surveys used transoesophageal echocardiography to assess the point prevalence of TE following Fontan surgery [22 – 24]. The studies reported prevalences of 17, 20 and 33% respectively. All studies demonstrated an increased sensitivity with transoesophageal compared to transthoracic echocardiography. These studies highlight the importance of using the appropriate diagnostic test to determine the incidence of thrombosis in any population. In cohort studies which had TE (venous thrombosis, arterial emboli or both) as a primary outcome measure the duration of follow up varied considerably. The reported incidence of venous thrombosis ranged from 3 to 19% and the incidence of stroke ranged from 3 to 19% [25 – 32]. Retrospective cohort studies not primarily directed at TE as an outcome have reported cumulative risk of venous thrombosis ranging from 0 to 20% [33 – 45].
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The frequency of TE was increased in recent studies compared to earlier studies, reflecting increased survival, longer duration of follow up, improved diagnostic tests, or increased awareness of the potential for thrombosis. The retrospective nature of the studies, frequent lack of sensitive diagnostic tests and limited follow up not only account for variation in reported incidences, but suggest that the reported frequencies of TE following Fontan surgery are minimal estimations. In general, information in the literature on the management and outcome of TE post-Fontan is scarce and often poorly documented. Previous reviews of the literature have reported that total resolution of thrombosis was achieved in only 48% of cases. Death occurred in 25% despite aggressive treatment. Follow up duration for these patients varied from 1 month to 5 years [23,24,26 –29,32,41,42, 46 – 58]. Given the lack of good data specifically related to outcome of thrombosis following Fontan surgery, it is worthwhile considering the outcome of venous thrombosis and stroke in children with congenital heart disease (CHD) in general. The Canadian Childhood Thrombophilia Registry has provided the largest prospective data base of pediatric venous TE, with a mean follow up time of 2.36 years. CHD was the underlying disease process in 75 of the 405 children (19%) reported with venous TE. The TE associated mortality in the CHD subgroup was 7%. Morbidity (post-phlebitic syndrome and TE recurrence) was 23% [59]. The Canadian Stroke Registry identified CHD as the most common identifiable cause in a cohort of 165 children with arterial ischaemic stroke. Thirty six percent of children with stroke had underlying CHD. In the entire stroke registry cohort, only 22% of children fully recovered. Sixty six percent had residual neurological defects and/or seizures [60]. Thus thromboembolic complications in children after Fontan surgery appear to be frequent and with significant clinical implications. This has lead to attempts to stratify STUDY OUTLINE Patient enrollment Fontan Procedure Randomisation immediately post surgery Heparin / warfarin Target INR 2-3
Aspirin 5mg/kg/dy
TTE/TOE at 3 months Monitor for clinical thrombosis, embolism or bleeding TTE/TOE at 2 years Study completion Fig. 2. Study schema for Fontan A trial, designed to determine the optimal primary antithrombotic prophylaxis agents following Fontan surgery.
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P. Monagle / Progress in Pediatric Cardiology 21 (2005) 17 – 21
children according to thromboembolic risk. However, no clear risk factors have been established yet by well designed studies. Further, consideration of the role for primary prophylaxis is the source of considerable ongoing debate. The options for primary prophylaxis include routine prophylactic anticoagulation with warfarin or antiplatelet agents. All anticoagulants increase the risk of bleeding. The risks in children after Fontan surgery are unknown. Clearly patients receiving warfarin will have higher probability of bleeding complications compared to those receiving aspirin. Recent Australian data suggests that with a well coordinated pediatric anticoagulation clinic the annual risk of major bleeding in children on warfarin can be reduced to 0.05% per patient year. Warfarin requires regular monitoring, which can have a significant impact on family life [61,62]. Recent reports raise the prospect of warfarin causing reduced bone density in children although further studies are required to confirm this effect [63]. At this time there are no convincing data that any prophylactic antithrombotic regimen is effective in reducing TE. The current multi centre Australian and Canadian randomized controlled trial, comparing heparin/warfarin anticoagulation to aspirin therapy after Fontan surgery (see Fig. 2 for study schema) will provide the best evidence to date about the true incidence of post Fontan thrombosis in patients receiving prophylaxis, as well as the safety and efficacy of each therapeutic option. Further trials will be required to delineate the optimal prophylactic therapy. In the meantime, current recommendations suggest aspirin (5 mg/ kg/day) or therapeutic heparin followed by vitamin K antagonists to achieve a target INR of 2.5 (range 2 to 3). The optimal duration of therapy is unknown. Whether patients with fenestrations require more intensive therapy until fenestration closure is unknown.
4. Conclusions Modern cardiac surgery has improved the survival for many children with congenital heart disease. Thrombosis has long been recognized as a significant complication, which is associated with important morbidity and mortality. Blalock –Taussig shunts, Glenn and Fontan procedures are arguably the most significant cardiac surgical procedures which are complicated by thrombosis. Despite this, and despite the incredible advances in surgical techniques, there is a frightening lack of good data to support or refute the role of antithrombotic prophylaxis following these procedures. There is an urgent need for the value and importance of well designed randomized trials to be understood by physicians and surgeons involved in the care of children with congenital heart disease. Case reports, case series, and retrospective observational studies will not adequately answer the questions at hand. The current Fontan A study, despite its limitations, demonstrates the feasibility of
performing multi centre randomized trials in such children. Unless many such trials are performed in the coming years, unnecessary adverse outcomes will continue to occur. The current uncertainty around the optimal primary prophylaxis regimes should be addressed such that generations of future children requiring cardiac surgery do so with minimal risk of thrombosis.
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[43] Annecchino F. Fontan repari for tricuspid atresia: experience with 50 patients. Ann Thorac Surg 1988;45:430 – 6. [44] Mair D, Rice M, Hagler D, Puga F, McGoon D, Danielson G. Outcome of the Fontan procedure in patients with tricuspid atresia. Circulation 1985;72(3 Pt. 3):1188 – 92. [45] Quinones J, DeLeon S, Bell T, et al. Fenestrated Fontan procedure: evolution of technique and occurrence of paradoxical embolism. Pediatr Cardiol 1997;18(3):218 – 21. [46] Dobell A, Trusler G, Smallborn J, Williams W. Atrial thrombi after the Fontan operation. Ann Thorac Surg 1986;42(6):664 – 7. [47] Fletcher S, Case C, Fyfe D, Gillette P. Clinical spectrum of venous thrombi after modified Fontan procedure. Am J Cardiol 1991;68(17): 1721 – 2. [48] Mahoney L. Thrombolytic treatment with streptokinase for late intraatrial thrombosis after modified Fontan procedure. Am J Cardiol 1988;62(4):343 – 4. [49] Beitzke A, Zobel G, Zenz W, Gamillscheg A, Stein J. Catheterdirected thrombolysis with recombinant tissue plasminogen activator for acute pulmonary embolism after Fontan operation. Pediatr Cardiol 1994;17(6):410 – 2. [50] Kao J, Alejos J, PW G, Williams R, Shannon K, Laks H. Conversion of atriopulmonary to cavopulmonary anastomosis in management of late arrhythmias and atrial thrombosis. Ann Thorac Surg 1994; 58(5):1510 – 4. [51] Sharratt G, Lacson A, Cornel G, Virmani S. Echocardiography of intracardiac filling defects in infants and children. Pediatr Cardiol 1986;7(4):189 – 94. [52] Lam J, Neirotti R, Becker A, Planche C. Thrombosis after the Fontan procedure: transoesophageal echocardiography may replace angiocardiography. J Thorac Cardiovasc Surg 1994;108(1):194 – 5. [53] Putnam J, Lemmer J, Rocchini A, Bove E. Embolectomy for acute pulmonary artery occlusion following Fontan procedure. Ann Thorac Surg 1988;45(3):335 – 6. [54] Hedrick M, Elkins R, Knott-Craig C, Razook J. Successful thrombectomy for thrombosis of the right side of the heart after the Fontan operation. J Thorac Cardiovasc Surg 1992;105(2):297 – 301. [55] Downing T. Pulmonary artery thrombosis associated with anomalous pulmonary venous connection: an unusual complication following the modified Fontan procedure. J Thorac Cardiovasc Surg 1985;90(3): 441 – 3. [56] Asante-Korang A. Thrombolysis with tissue type plasminogen activator following cardiac surgery in children. Int J Cardiol 1992; 35(3):317 – 22. [57] Dajee H, Deutsch L, Benson L, Perloff J, Laks H. Thrombolytic therapy for superior vena caval thrombosis following superior vena cava-pulmonary anastomosis. Ann Thorac Surg 1984;38(6):637 – 9. [58] Wilson D. Systemic thromboembolism leading to myocardial infarction and stroke after fenestrated total cavopulmonary connection. Br Heart J 1995;73(5):483 – 5. [59] Monagle P, Adams M, Mahoney M, et al. Outcome of paediatric thromboembolic disease: a report from the Canadian childhood thrombophilia registry. Pediatr Res 2000;47(6):763 – 6. [60] deVeber G, Adams M, Andrew M, et al. Canadian pediatric ischemic stroke registry. analysis III (Abstract). Thromb Haemost 1995;73. [61] Newall F, Savoia H, Campbell J, Monagle P. Anticoagulation clinics for children achieve improved warfarin management. Thromb Res 2004;114(1):5 – 9. [62] Andrew M, Marzinotto V, Brooker L, et al. Oral anticoagulant therapy in pediatric patients: a prospective study. Thromb Haemost 1994; 71(3):265 – 9. [63] Barnes C, Newall F, Wong P, et al. Reduced bone density in children on long term warfarin therapy. Pediatr Res 2005;57:578 – 81.
Thrombosis in children with BT shunts, Glenns and Fontans Paul Monagle * Department of Haematology, Royal Children’s Hospital Chair, Head of Department of Pathology, University of Melbourne, Flemington Rd. Melbourne, Victoria 3052, Australia Available online 22 November 2005
Abstract Children with congenital heart disease (CHD) constitute a major proportion of children seen in tertiary hospitals with thromboembolic disease (TE). Three common surgical procedures are the Blalock – Taussig (BT) shunt, Glenn shunt and the Fontan surgery. All of these procedures can result in TE. There are few well designed studies in the literature determining the epidemiology of TE in these cohorts, however, TE has been diagnosed in children, especially following the BT shunt and the Fontan surgery. The best approach to treat or prevent TE complications in these cohorts of children has not been determined. Clinical studies are urgently required to provide evidence based recommendations for treatment and prophylaxis of TE. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Pediatrics; Congenital heart disease; Blalock – Taussig shunts; Glenn shunts; Fontan procedure; Thrombosis
Congenital heart disease (CHD), with a wide spectrum of severity, affects approximately 1% of all live births. The majority of congenital cardiac structural abnormalities occur in otherwise healthy children and total correction of the cardiac lesion usually results in a normal productive lifespan. Thromboembolic disease (TE) has been termed the new epidemic of pediatric tertiary care hospitals. Nowhere is this more evident than in cardiac and cardiac surgical children. Improved survival for these children over the last decade has been the result of tremendous advances in surgical techniques, availability of new drugs and new applications for old drugs, and developments in critical and supportive care. Despite this, one of the most frequent complications seen in survivors of CHD is TE, which include venous, arterial and intracardiac TEs, pulmonary embolism, and embolism to the central nervous system. Venous TEs in children with CHD have a mortality of approximately 7%. Morbidity in the form of post phlebitic syndrome and recurrent venous TEs occurred in 23% of children. Children with CHD constitute a major proportion of children seen in tertiary hospitals with TE. Recent data show that almost 50% of infants less than 6 months, and 30% of * Tel.: +61 3 93455919; fax: +61 3 93491819. E-mail address: [email protected]. 1058-9813/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ppedcard.2005.09.003
older children who suffer venous TE have underlying cardiac disorders. Similarly, almost 70% of infants (< 6 months) and 30% children who suffer arterial TE have underlying cardiac defects. In addition, the majority of children on primary anticoagulant prophylaxis are being treated for complex CHD or severe acquired cardiac illness. Three common cardiac surgical procedures are Blalock– Taussig (BT) shunts, Glenn procedures, and Fontan surgery. In many patients these surgeries will be performed sequentially. The initial BT shunt during the neonatal period, followed by a Glenn procedure as the first stage towards a final Fontan procedure which is the definitive palliative surgery. Thrombosis can occur as a complication of each procedure, however the implications of thrombosis differ for each surgical procedure, as does the management and potential outcome. There remains little conclusive evidence to support the optimal treatment strategies for thrombotic complications of these procedures. This paper will discuss thrombosis as a complication of each of these surgical procedures.
1. Blalock –Taussig (BT) shunt BT shunts are commonly performed in the neonatal period to increase pulmonary blood flow. BT shunts may be
18
P. Monagle / Progress in Pediatric Cardiology 21 (2005) 17 – 21
performed as a single palliative procedure with planned later more definitive surgery, or as part of a more complex surgical intervention (e.g. Norwood procedure). In classic BT shunts, the subclavian artery is anastomosed directly to the ipsilateral pulmonary artery. The procedure is usually performed on right side, unless there is a right sided aortic arch, in which case the shunt is performed on the left. In contrast, for a modified BT shunt a Gore-tex tube graft is placed between the subclavian artery and the ipsilateral pulmonary artery. The Gore-tex tube may be as small as 3 mm diameter, depending on the size of the infant, but is usually 3.5 or 4 mm in diameter. The natural history of BT shunts has been assessed using angiography. Godart et al. assessed BT shunt growth and development of stenosis and distortion in 78 patients at a mean follow up time of 51 months [1]. They found that growth of the pulmonary arteries occurred but did not exceed the normal growth of the pulmonary arterial tree. However, a shunt procedure could cause distortion and stenosis of the pulmonary artery which may have important implications for future corrective surgical intervention. Patients with BT shunts may have reduced peripheral pulses in the ipsilateral arm, and may have measurably reduced growth of the arm. This can be of significance when assessing for post thrombotic syndrome which may occur in the upper limbs secondary to central venous thrombosis (see Fig. 1). Blockage of the BT shunt will compromise pulmonary blood flow and is often a major clinical event requiring immediate surgery. The incidence of thrombotic occlusion of BT shunts in the literature ranges from 1 to 17% [2– 16]. Risk factors for patency and stenosis include the age of the patient and graft size [2,3]. Diagnosis is usually
Fig. 1. Teenage boy with previous BT shunt on the right side, and venous thrombosis in the left brachial/axillary vein. Note the difference in size of the arms. There was noticeable reduced hair growth on the right arm. The boy was left handed.
clinical, although echocardiography, and angiography can be of value. There is no consistent approach to the prevention of thrombosis of BT shunts. Many investigators use antithrombotic therapy beginning with therapeutic doses of heparin and followed by low dose aspirin (1 to 10 mg/kg/ day) [15], although others recommend intraoperative heparin with no further anticoagulation [16]. There is no data from randomized trials to demonstrate clinical superiority of either approach. Children who develop acute BT shunt occlusion usually require some form of intervention which include thrombolytic therapy and/or stenting. Local thrombolytic therapy with tissue plasminogen activator and streptokinase have been used successfully in some children [9,17]. Angioplasty, balloon dilation, stent implantation [6,18] and repeat surgery [2,4] are other therapeutic options. The latter usually require subsequent anticoagulation therapy.
2. Glenn procedure (BCPS) The bidirectional cavopulmonary shunt(BCPS) or bidirectional Glenn procedure is an end (superior vena cava) to side (right pulmonary artery) venous shunt. This is a palliative procedure that increases oxygen saturation, but without increasing left ventricular work, and is usually performed in children with univentricular cardiac physiology, as the first stage of the two stage Fontan procedure. The IVC is unchanged after a Glenn procedure. The implications with respect to thrombosis are that, following a Glenn procedure, the SVC blood flows directly to the lungs without any assistance from the heart. Hence any reduction in SVC flow, due to thrombus occlusion, will dramatically reduce pulmonary blood flow. Pulmonary emboli are of specific concern in that if the pulmonary vascular resistance is increased, the patient may become unsuitable for a Fontan completion, which limits long term survival significantly in the absence of cardiac transplantation. Blood flow from the IVC still bypasses the lungs, meaning that any thrombus in the lower venous system can give rise to paradoxical emboli. Collaterals around central venous thrombosis may interfere with the ability to complete the Fontan surgery. The threat of being unable to complete the Fontan may be a justification for more aggressive antithrombotic therapy (thrombolysis or surgery) than might otherwise be indicated. Thrombotic complications following the Glenn shunt are infrequently reported [19 – 21]. There appears to be no data to support the need for routine thromboprophylaxis. However, once again, the fact that many patients subsequently proceed to Fontan procedures has led to some suggestions that thromboprophylaxis is warranted after a Glenn shunt to reduce the risk of thrombosis in the pulmonary vasculature, hence increasing the likelihood of successful conversion to a full Fontan circuit. Current clinical practices vary, and
P. Monagle / Progress in Pediatric Cardiology 21 (2005) 17 – 21
include: no anticoagulation, heparin followed by aspirin, heparin followed by warfarin therapy. There is no evidence to support a preference for any of these approaches at this time.
3. Fontan procedure There are numerous modifications of the Fontan procedure, but the basic principles remain the same. Both the SVC (usually done in a first stage BCPS) and the IVC are anastomosed to the pulmonary arteries. Hence the pulmonary blood flow is totally passive, depending on venous flow mechanisms without any cardiac pump assistance. The univentricle is then able to function as a left ventricle, providing systemic blood flow. Post operatively, many patients have deliberate, limited, right to left interatrial shunting via a ‘‘fenestration’’. The blood flow in such cases increases the risk of paradoxical emboli. The implications with respect to thrombosis following Fontan surgery are significant. First, the presence of right to left communication continues the potential for paradoxical emboli. Second, any pulmonary emboli which increase pulmonary vascular resistance have an accentuated impact on pulmonary blood flow, as the pulmonary pressure cannot be increased to overcome a pressure gradient. The Fontan circuit makes the diagnosis of pulmonary emboli particularly difficult. Depending on the attachment of the SVC and IVC to the pulmonary arteries, isotope may need to be injected into both an arm and a leg to achieve full lung perfusion scanning. As for patients with severe pulmonary hypertension having ventilation/perfusion scans, the transient obstruction of pulmonary capillaries by the macro-aggregated isotope labeled albumin may rarely precipitate a hypoxic episode. Finally, depending on the exact type of Fontan surgery, the risk of late (many years later) thrombosis associated with dysrythmias may be increased. The incidence of thrombosis after Fontan surgery has not been determined by prospective trials. Three cross sectional surveys used transoesophageal echocardiography to assess the point prevalence of TE following Fontan surgery [22 – 24]. The studies reported prevalences of 17, 20 and 33% respectively. All studies demonstrated an increased sensitivity with transoesophageal compared to transthoracic echocardiography. These studies highlight the importance of using the appropriate diagnostic test to determine the incidence of thrombosis in any population. In cohort studies which had TE (venous thrombosis, arterial emboli or both) as a primary outcome measure the duration of follow up varied considerably. The reported incidence of venous thrombosis ranged from 3 to 19% and the incidence of stroke ranged from 3 to 19% [25 – 32]. Retrospective cohort studies not primarily directed at TE as an outcome have reported cumulative risk of venous thrombosis ranging from 0 to 20% [33 – 45].
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The frequency of TE was increased in recent studies compared to earlier studies, reflecting increased survival, longer duration of follow up, improved diagnostic tests, or increased awareness of the potential for thrombosis. The retrospective nature of the studies, frequent lack of sensitive diagnostic tests and limited follow up not only account for variation in reported incidences, but suggest that the reported frequencies of TE following Fontan surgery are minimal estimations. In general, information in the literature on the management and outcome of TE post-Fontan is scarce and often poorly documented. Previous reviews of the literature have reported that total resolution of thrombosis was achieved in only 48% of cases. Death occurred in 25% despite aggressive treatment. Follow up duration for these patients varied from 1 month to 5 years [23,24,26 –29,32,41,42, 46 – 58]. Given the lack of good data specifically related to outcome of thrombosis following Fontan surgery, it is worthwhile considering the outcome of venous thrombosis and stroke in children with congenital heart disease (CHD) in general. The Canadian Childhood Thrombophilia Registry has provided the largest prospective data base of pediatric venous TE, with a mean follow up time of 2.36 years. CHD was the underlying disease process in 75 of the 405 children (19%) reported with venous TE. The TE associated mortality in the CHD subgroup was 7%. Morbidity (post-phlebitic syndrome and TE recurrence) was 23% [59]. The Canadian Stroke Registry identified CHD as the most common identifiable cause in a cohort of 165 children with arterial ischaemic stroke. Thirty six percent of children with stroke had underlying CHD. In the entire stroke registry cohort, only 22% of children fully recovered. Sixty six percent had residual neurological defects and/or seizures [60]. Thus thromboembolic complications in children after Fontan surgery appear to be frequent and with significant clinical implications. This has lead to attempts to stratify STUDY OUTLINE Patient enrollment Fontan Procedure Randomisation immediately post surgery Heparin / warfarin Target INR 2-3
Aspirin 5mg/kg/dy
TTE/TOE at 3 months Monitor for clinical thrombosis, embolism or bleeding TTE/TOE at 2 years Study completion Fig. 2. Study schema for Fontan A trial, designed to determine the optimal primary antithrombotic prophylaxis agents following Fontan surgery.
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P. Monagle / Progress in Pediatric Cardiology 21 (2005) 17 – 21
children according to thromboembolic risk. However, no clear risk factors have been established yet by well designed studies. Further, consideration of the role for primary prophylaxis is the source of considerable ongoing debate. The options for primary prophylaxis include routine prophylactic anticoagulation with warfarin or antiplatelet agents. All anticoagulants increase the risk of bleeding. The risks in children after Fontan surgery are unknown. Clearly patients receiving warfarin will have higher probability of bleeding complications compared to those receiving aspirin. Recent Australian data suggests that with a well coordinated pediatric anticoagulation clinic the annual risk of major bleeding in children on warfarin can be reduced to 0.05% per patient year. Warfarin requires regular monitoring, which can have a significant impact on family life [61,62]. Recent reports raise the prospect of warfarin causing reduced bone density in children although further studies are required to confirm this effect [63]. At this time there are no convincing data that any prophylactic antithrombotic regimen is effective in reducing TE. The current multi centre Australian and Canadian randomized controlled trial, comparing heparin/warfarin anticoagulation to aspirin therapy after Fontan surgery (see Fig. 2 for study schema) will provide the best evidence to date about the true incidence of post Fontan thrombosis in patients receiving prophylaxis, as well as the safety and efficacy of each therapeutic option. Further trials will be required to delineate the optimal prophylactic therapy. In the meantime, current recommendations suggest aspirin (5 mg/ kg/day) or therapeutic heparin followed by vitamin K antagonists to achieve a target INR of 2.5 (range 2 to 3). The optimal duration of therapy is unknown. Whether patients with fenestrations require more intensive therapy until fenestration closure is unknown.
4. Conclusions Modern cardiac surgery has improved the survival for many children with congenital heart disease. Thrombosis has long been recognized as a significant complication, which is associated with important morbidity and mortality. Blalock –Taussig shunts, Glenn and Fontan procedures are arguably the most significant cardiac surgical procedures which are complicated by thrombosis. Despite this, and despite the incredible advances in surgical techniques, there is a frightening lack of good data to support or refute the role of antithrombotic prophylaxis following these procedures. There is an urgent need for the value and importance of well designed randomized trials to be understood by physicians and surgeons involved in the care of children with congenital heart disease. Case reports, case series, and retrospective observational studies will not adequately answer the questions at hand. The current Fontan A study, despite its limitations, demonstrates the feasibility of
performing multi centre randomized trials in such children. Unless many such trials are performed in the coming years, unnecessary adverse outcomes will continue to occur. The current uncertainty around the optimal primary prophylaxis regimes should be addressed such that generations of future children requiring cardiac surgery do so with minimal risk of thrombosis.
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