1450
stimulation due to intense irritation of the face in primary HVZ infection, combined with production of systemic antibodies to HVZ and antigen-antibody complexes, produces the conditions in which vasculopathy and in-situ thrombosis may occur. Sympathetic stimulation may also result from viral invasion of the superior cervical ganglion by retrograde infection. The delay between primary infection and onset of hemiparesis is explained by the time taken for antibody-antigen complexes to form and to induce thrombosis in the affected artery. However, the absence of angiographic evidence of vasculitis in two of the patients would be unexpected if formation of antigen-antibody complexes were crucial to the development of this disorder. Another difficulty is that there is no evidence that patients with delayed-onset hemiparesis following primary HVZ infection have especially severe facial eruptions or corneal involvement, and are therefore subject to intense sympathetic stimulation. The clinical course and angiographic appearances in delayed-onset hemiparesis are also very different from those of Moyamoya disease. If sympathetic stimulation at the time of primary infection rather than invasion of the superior cervical ganglion is important in pathogenesis, it becomes difficult to explain how such stimulation could persist and play a part in production of hemiparesis weeks later. For a more likely explanation one may have to turn to the pathogenetic mechanisms involved in delayed-
hemiparesis ipsilateral to herpes zoster ophthalmicus. Eidelberg3 reported three patients with zoster of the ophthalmic branch of the trigeminal nerve followed 3-6 months later by contralateral hemiparesis. Describing these patients and previously reported cases, he recorded that the interval between facial zoster and hemiparesis was 5 weeks to 6 months. In two of the three cases, HVZ antigen was detected in the media of the middle cerebral artery ipsilateral to onset
the site of HVZ infection and contralateral to the hemiparesis. The presence of viral antigen in vessel media was thought to be due to direct passage along the intracranial branches of the trigeminal nerve. There are extensive trigemino-vascular connections, especially to the middle and anterior cerebral arteries, with nerve fibres extending to the adventitia/media junction. The sympathetic nervous system pathway also runs parallel to the trigemino-vascular system, which raises the possibility of direct spread as suggested by Bodensteiner et al. Bodensteiner and colleagues considered this a possible mechanism when suggesting involvement of the sympathetic nervous system in primary HVZ infection and delayed hemiparesis. Endothelial cell injury could result from the presence of HVZ in the media of the blood vessels, which would lead to vasculopathy and in-situ thrombosis without necessarily producing evidence A of similar vasculitis. angiographic mechanism-ie, retrograde infection of the trigeminal or sympathetic nervous system-could be proposed
for
delayed-onset hemiparesis following primary
infection. In children with delayed-onset hemiparesis, there may be varicella infection of the trigeminal nerve and its facial and vascular branches, which subsequently extends to involve the media of the carotid artery and its branches (which have dense trigeminal innervation) and predisposes to in-situ thrombosis. The presence of circulating immune complexes or involvement of the sympathetic nervous system is not necessary if the mechanism of hemiparesis is similar in primary and secondary HVZ infections. Delay in onset would result from the time taken for the vascular media to be infected. There is no knowing whether the mechanisms proposed by Bodensteiner et all or that put forward by Eidelberg3 to explain contralateral hemiparesis following ophthalmic zoster will prove to be correct. Nonetheless, Bodensteiner et al have described a clinical entity that has received too little attention. Recognition of this association is important because of the very wide differential diagnosis of acute hemiparesis in childhood and because of the many patients in whom no cause can be found. The most important aspect of delayed-onset hemiparesis following primary infection is that, if no other cause of hemiparesis is found, a good prognosis can be given. It is, however, important that all children with or without preceding varicella infection who present with delayed-onset hemiparesis receive full radiological and haematological investigation to exclude other causes of stroke-the fact that one event bears a temporal relation to another event does not mean that one causes the other. JB, Hille MR, Riggs JE. Clinical features of vascular thrombosis following varicella. Am J Dis Child 1992; 146: 100-02. 2. Gordon N, Isler W. Childhood Moyamoya disease. Dev Med Child Neurol 1989; 31: 98-107. 3. Eidelberg D, Sotrel A, Horoupian DS, Neumann PE, Pumarola-Sune T, Pnce RW. Thrombotic cerebral vasculopathy associated with herpes zoster. Ann Neurol 1986; 19: 7-14. 1. Bodensteiner
Fontan
procedure
The Fontan operation,l or one of its many modifications, has become the definitive palliative procedure offered to patients with complex congenital
heart disease in whom there is no prospect of establishing a normal biventricular circulation.2 Essentially, the Fontan circulation converts the parallel pulmonary and systemic circulations in the preoperative state into a more normal arrangement of two circulations in series. This is done by connecting directly the right atrium to the pulmonary artery, or alternatively by joining the superior caval vein (directly) and inferior caval vein (via an intra-atrial baffle) to the pulmonary arteries (a so-called total cavopulmonary connection). The potential benefits are obvious: arterial oxygen saturation returns to normal, while a reduction in the long-term volume load placed on the systemic ventricle may
1451
prevent the
of atrioventricular valve regurgitation and ventricular failure. However, these benefits are gained at cost. There are no valves and there is no effective ventricle in the pulmonary circulation. Consequently, flow of blood through the lungs largely depends on the modest pressure gradient between the systemic veins and the left atrium.3 Any factor that reduces this gradient will influence both early survival and late outcome. In 1977, Choussat and his colleagues4 defined ten criteria that would be met by the ideal candidate for a Fontan procedure. With increasing experience, cardiac surgeons have come to recognise that some of these criteria are more important than others. For example, the importance of both the gross pulmonary architecture and the pulmonary vascular resistance in determining outcome after the operation cannot be overemphasised. A mean preoperative pulmonary arterial pressure above 15 mm Hg adversely affects survival, as does a preoperative pulmonary vascular resistance greater than 2 units per m2. Systemic ventricular hypertrophy also adversely influences outcome. Choussat et al concentrated on ventricular systolic function,4 but there is increasing evidence that impaired ventricular diastolic function may be important in determining risk from the Fontan operation.6,7 Although there is little demonstrable change in systolic function, the Fontan operation has profound effects on diastolic function of the systemic ventricle. It reduces ventricular preload and decreases cavity dimensions, so there is a pronounced increase in wall thickness after the procedure. These effects have been documented at the time of the transition to the Fontan circulation in the operating theatre.8 Diastolic ventricular compliance is usually normal but uncoordinated ventricular wall motion impairs relaxation and reduces ventricular filling in early diastole, and these abnormalities persist during short and medium term follow-up.9 These fmdings may partly account for the depressingly high perioperative mortality still reported in centres with extensive experience. Review of surgical results suggests that children with a double-inlet left ventricle have a higher mortality than do those with tricuspid atresia, while an early mortality of 34% has been reported in patients in whom the systemic ventricle has right ventricular morphological features.10,11 Just as worrying are the results of longer term follow-up: there is a late hazard phase, with an increasing mortality at the start of the sixth postoperative year, usually related to "circulatory failure" .12 How can we improve on the operative results? First, since a low cardiac output as a result of reduced pulmonary flow is usually the cause of peroperative death, any means of augmenting output in this critical phase will have beneficial effects. No matter what type of surgical anastomosis is used, fenestration of the intra-atrial baffle, which increases systemic ventricular preload at the expense of arterial desaturation, is perhaps the greatest single advance in
development
the management of these patients.13 This procedure has led to a striking improvement in the immediate postoperative course, such that survival can now be expected even in patients previously thought to be at high risk. Subsequently, the fenestration can be easily closed, if necessary, by an umbrella or clamshell device inserted via a catheter. 14 A second area offering scope for improvement concerns flow of blood to the lungs. Positive pressure ventilation has a predictably deleterious effect on the flow of blood into the lungs, yet most postoperative regimens use this approach. Negative extrathoracic pressure ventilation could, by obviating the deleterious effects of positive pressure ventilation as well as by augmenting systemic venous return, be beneficial. The use of such a technique has been explored by Penny et al. 15 Early data suggest that this can double the flow of blood to the lungs (and hence cardiac output). A third possibility for improvement lies in the surgical procedure itself. Bypassing the right atrium, by use of a total has theoretical connection, cavopulmonary over the standard Fontan procedure.16 advantages Balaji et al 17 found that the frequency of arrhythmias was lower in patients after construction of a total cavopulmonary connection than after the Fontan operation, although follow-up in this study was short. These researchers also reported a lower mortality in the patients who underwent total cavopulmonary connection, although the post-Fontan mortality in their centre was very high (15% vs 34%). We now need to improve our understanding of the physiology of the Fontan circulation and determine how it can be manipulated, especially in the early postoperative period. Longer periods of follow-up will clarify the relative merits of the various modifications of the Fontan procedure, and show whether they have clear advantages over the original
approach. 1. Fontan S, Baudet E. Surgical repair of tricuspid atresia. Thorax 1971; 26: 240-48. 2. DeLeon SY, Ilbawi MN, Idriss SS, et al. Fontan-type operation for complex lesions. J Thorac Cardiovasc Surg 1986; 92: 1029-37. 3. Sullivan ID, Taylor JFN. Hearts with one ventricle: current concepts in management. Arch Dis Child 1989; 64: 166-71. 4. Choussat A, Fontan S, Vesse P, Vallot F, Chauve A, Bricaud H. Selection criteria for Fontan’s procedure. In: Anderson RH, Shinebourne EA, eds. Paediatric cardiology. Edinburgh: Churchill Livingstone, 1977: 559-66. 5. Fontan S, Fernandez G, Ebner A. Risk factors for the Fontan procedure. In: Crupi G, Parenzan L, Anderson RH, eds. Perspectives in pediatric cardiology. New York: Futura, 1989: 183-263. 6. Kirkland JK, Blackstone EH, Kirkland JW, Pacifico AD, Bargeron LM. The Fontan operation: ventricular hypertrophy, age and date of operation as risk factors. J Thorac Cardiovasc Surg 1986; 92: 1049-64. 7. Redington AN, Knight B, Oldershaw PJ, Shinebourne EA, Rigby ML. Left ventricular function in double inlet left ventricle before the Fontan operation: comparison with tricuspid atresia. Br Heart J 1988; 60: 324-31. 8. Penny DJ, Lincoln C, Shore DF, Xiao HB, Rigby ML, Redington AN. The early response of the systemic ventricle during transition to the
Fontan circulation: an acute hypertrophic cardiomyopathy? Cardiology in the Young 1992; 2: 78-84. 9. Penny DJ, Rigby ML, Redington AN. Abnormal patterns of intraventricular flow and diastolic filling after the Fontan operation: evidence for incoordinate ventricular wall motion. Br Heart J 1991; 66: 375-78.
1452
10. Coles JG, Kielmanowicz S, Freedom EM, et al. Surgical experience with the modified Fontan procedure. Circulation 1987; 76 (suppl): 61-66. 11. Matsuda H, Kawashima Y, Tishimoto H, et al. Problems in the modified Fontan operation for univentricular heart of the right ventricular type. Circulation 1987; 76 (suppl): 45-52. 12. Fontan S, Kirkland JW, Fernandez G, et al. Outcome after a "perfect" Fontan operation. Circulation 1990; 81: 1520-36. 13. Laks H, Pearl JM, Hass GS, et al. Partial Fontan: advantages of an adjustable interatrial communication. Ann Thorac Surg 1991; 52: 1084-95. 14. Bridges ND, Lock JE, Castineda AR. Baffle fenestration with subsequent transcatheter closure. Circulation 1990; 82: 1681-89. 15. Penny DJ, Hayek Z, Rawle P, Rigby ML, Redington AN. Ventilation with external high-frequency oscillation around a negative baseline increases pulmonary blood flow after the Fontan operation. Cardiology in the Young 1992; 2: 277-80. 16. DeLaval MR, Kilner P, Gewillig M, Bull C. Total cavopulmonary connection: a logical alternative to atrial pulmonary connection for complex Fontan operations. J Thorac Cardiovasc Surg 1988; 96: 682-95. 17. Balaji S, Gewellig M, Bull C, DeLeval MR, Deanfield JE. Arrhythmia after the Fontan procedure: comparison of total cavopulmonary connection and atriopulmonary connection. Circulation 1991; 84 (suppl): 162-66.
Medicinal Euroadvertising for 1993 Readers of the London edition of The Lancet who peruse the journal to the very last page will have noticed a strongly worded statement that requires advertisers to observe the provisions of, among other pieces of legislation, the Medicines Act 1968. But from Jan 1, 1993, the legally enforceable regulations that cover advertisements will be substantially strengthened and extended by European Community Council Directive 92/28/EEC (see Lancet Feb 22, p 483), which intends to set minimum standards on the advertising of medicinal products for human use throughout the Community. What will this new law mean for pharmaceutical companies and medical journals, and what responsibilities will it place on the doctor in his or her dealings with company
representatives? An example of how this EC directive might work is provided in the latest issue of the Drug and Therapeutics Bulletin.1 Etidronate (Didronel PMO, Norwich Eaton) is a bisphosphonate that is licensed in the UK for treatment of vertebral osteoporosis only. Yet, in advertising material that was sent to doctors in the UK earlier this year, the company answer their own question "who do I treat with Didronel PMO?" thus: "Postmenopausal women currently being treated for established osteoporosis; postmenopausal women with vertebral, wrist, or hip fractures due to osteoporosis; postmenopausal women who have X-ray evidence of osteoporosis; patients with clear signs and symptoms of established vertebral osteoporosis" (our italics). Only in the abbreviated prescribing information (in considerably smaller print) does the advertisement make clear that vertebral osteoporosis is the sole licensed indication. Such questionable claims could fall foul of the new EC directive.
existing British legislation,2 an advertisement is legal provided it is "not inconsistent with the particulars contained in the data sheet". The According
ruling is more definite: "All parts of the advertising... must comply with the particulars listed in the summary of product characteristics". The
new
EC
advertisement must go no further than the data sheet in its content. If an advertisement is deemed to exceed the licensed indications for a particular drug, the 1993 EC directive will allow member states to "confer upon the courts or administrative authorities powers to require in addition the enabling them publication of a corrective statement". For Didronel PMO, if the advertisement had appeared next year and legislation had been enacted, would this mean a press statement; a formal retraction in a subsequent advertisement; or an obligation on medical journals ...
publish a "corrective statement"? Since advertisements will be subject to legally enforceable modification and can rapidly become out of date, "any documentation relating to a medicinal product ... shall state the date on which it was drawn up or last revised". Two other important issues are addressed in the EC directive. First, doctors will not be allowed to "solicit or accept any inducement" from a drug company to prescribe or supply a medicinal product. Guidelines exist, such as those from the Association of the British Pharmaceutical Industry, about what company representatives are allowed to offer as inducements, but EC law will place a direct responsibility on doctors to refuse "gifts, pecuniary advantages, or benefits in kind ... unless they are inexpensive and relevant to the practice of medicine or pharmacy". Furthermore, in the UK Pharmaceutical Price Regulation Scheme, companies have been allowed to differentiate between "sales promotion" and "information expenses" (education). Since limits exist on the amount of money that can be spent on promotion, educational activities (eg, sponsored international meetings for which all expenses are paid for by the company) have allowed the industry to offer inducements that can be budgeted for under information expenses. This accountancy ruse will be prevented under the new EC directive. Advertising "shall include in particular... sponsorship of promotional meetings ... sponsorship of scientific congresses... and payment of their travelling and accommodation expenses". The rationalisation of expenditure into a single category, with most of the promotion and education budget being classed as advertising, will severely limit the amount of money that can be spent on inducements to to
prescribe. The directive is littered with "shall" and "may" but places on the twelve EC countries an obligation to set up schemes to monitor advertising. Prior vetting is one way; many journals (including The Lancet) do this now editorially, and, at an official level that is what France practises.
to
1. Etidronate for vertebral osteoporosis after the menopause. Drug Ther Bull 1992; 30: 45-46. 2. The Medicines Act 1968. London: HM Stationery Office, 1968.
stimulation due to intense irritation of the face in primary HVZ infection, combined with production of systemic antibodies to HVZ and antigen-antibody complexes, produces the conditions in which vasculopathy and in-situ thrombosis may occur. Sympathetic stimulation may also result from viral invasion of the superior cervical ganglion by retrograde infection. The delay between primary infection and onset of hemiparesis is explained by the time taken for antibody-antigen complexes to form and to induce thrombosis in the affected artery. However, the absence of angiographic evidence of vasculitis in two of the patients would be unexpected if formation of antigen-antibody complexes were crucial to the development of this disorder. Another difficulty is that there is no evidence that patients with delayed-onset hemiparesis following primary HVZ infection have especially severe facial eruptions or corneal involvement, and are therefore subject to intense sympathetic stimulation. The clinical course and angiographic appearances in delayed-onset hemiparesis are also very different from those of Moyamoya disease. If sympathetic stimulation at the time of primary infection rather than invasion of the superior cervical ganglion is important in pathogenesis, it becomes difficult to explain how such stimulation could persist and play a part in production of hemiparesis weeks later. For a more likely explanation one may have to turn to the pathogenetic mechanisms involved in delayed-
hemiparesis ipsilateral to herpes zoster ophthalmicus. Eidelberg3 reported three patients with zoster of the ophthalmic branch of the trigeminal nerve followed 3-6 months later by contralateral hemiparesis. Describing these patients and previously reported cases, he recorded that the interval between facial zoster and hemiparesis was 5 weeks to 6 months. In two of the three cases, HVZ antigen was detected in the media of the middle cerebral artery ipsilateral to onset
the site of HVZ infection and contralateral to the hemiparesis. The presence of viral antigen in vessel media was thought to be due to direct passage along the intracranial branches of the trigeminal nerve. There are extensive trigemino-vascular connections, especially to the middle and anterior cerebral arteries, with nerve fibres extending to the adventitia/media junction. The sympathetic nervous system pathway also runs parallel to the trigemino-vascular system, which raises the possibility of direct spread as suggested by Bodensteiner et al. Bodensteiner and colleagues considered this a possible mechanism when suggesting involvement of the sympathetic nervous system in primary HVZ infection and delayed hemiparesis. Endothelial cell injury could result from the presence of HVZ in the media of the blood vessels, which would lead to vasculopathy and in-situ thrombosis without necessarily producing evidence A of similar vasculitis. angiographic mechanism-ie, retrograde infection of the trigeminal or sympathetic nervous system-could be proposed
for
delayed-onset hemiparesis following primary
infection. In children with delayed-onset hemiparesis, there may be varicella infection of the trigeminal nerve and its facial and vascular branches, which subsequently extends to involve the media of the carotid artery and its branches (which have dense trigeminal innervation) and predisposes to in-situ thrombosis. The presence of circulating immune complexes or involvement of the sympathetic nervous system is not necessary if the mechanism of hemiparesis is similar in primary and secondary HVZ infections. Delay in onset would result from the time taken for the vascular media to be infected. There is no knowing whether the mechanisms proposed by Bodensteiner et all or that put forward by Eidelberg3 to explain contralateral hemiparesis following ophthalmic zoster will prove to be correct. Nonetheless, Bodensteiner et al have described a clinical entity that has received too little attention. Recognition of this association is important because of the very wide differential diagnosis of acute hemiparesis in childhood and because of the many patients in whom no cause can be found. The most important aspect of delayed-onset hemiparesis following primary infection is that, if no other cause of hemiparesis is found, a good prognosis can be given. It is, however, important that all children with or without preceding varicella infection who present with delayed-onset hemiparesis receive full radiological and haematological investigation to exclude other causes of stroke-the fact that one event bears a temporal relation to another event does not mean that one causes the other. JB, Hille MR, Riggs JE. Clinical features of vascular thrombosis following varicella. Am J Dis Child 1992; 146: 100-02. 2. Gordon N, Isler W. Childhood Moyamoya disease. Dev Med Child Neurol 1989; 31: 98-107. 3. Eidelberg D, Sotrel A, Horoupian DS, Neumann PE, Pumarola-Sune T, Pnce RW. Thrombotic cerebral vasculopathy associated with herpes zoster. Ann Neurol 1986; 19: 7-14. 1. Bodensteiner
Fontan
procedure
The Fontan operation,l or one of its many modifications, has become the definitive palliative procedure offered to patients with complex congenital
heart disease in whom there is no prospect of establishing a normal biventricular circulation.2 Essentially, the Fontan circulation converts the parallel pulmonary and systemic circulations in the preoperative state into a more normal arrangement of two circulations in series. This is done by connecting directly the right atrium to the pulmonary artery, or alternatively by joining the superior caval vein (directly) and inferior caval vein (via an intra-atrial baffle) to the pulmonary arteries (a so-called total cavopulmonary connection). The potential benefits are obvious: arterial oxygen saturation returns to normal, while a reduction in the long-term volume load placed on the systemic ventricle may
1451
prevent the
of atrioventricular valve regurgitation and ventricular failure. However, these benefits are gained at cost. There are no valves and there is no effective ventricle in the pulmonary circulation. Consequently, flow of blood through the lungs largely depends on the modest pressure gradient between the systemic veins and the left atrium.3 Any factor that reduces this gradient will influence both early survival and late outcome. In 1977, Choussat and his colleagues4 defined ten criteria that would be met by the ideal candidate for a Fontan procedure. With increasing experience, cardiac surgeons have come to recognise that some of these criteria are more important than others. For example, the importance of both the gross pulmonary architecture and the pulmonary vascular resistance in determining outcome after the operation cannot be overemphasised. A mean preoperative pulmonary arterial pressure above 15 mm Hg adversely affects survival, as does a preoperative pulmonary vascular resistance greater than 2 units per m2. Systemic ventricular hypertrophy also adversely influences outcome. Choussat et al concentrated on ventricular systolic function,4 but there is increasing evidence that impaired ventricular diastolic function may be important in determining risk from the Fontan operation.6,7 Although there is little demonstrable change in systolic function, the Fontan operation has profound effects on diastolic function of the systemic ventricle. It reduces ventricular preload and decreases cavity dimensions, so there is a pronounced increase in wall thickness after the procedure. These effects have been documented at the time of the transition to the Fontan circulation in the operating theatre.8 Diastolic ventricular compliance is usually normal but uncoordinated ventricular wall motion impairs relaxation and reduces ventricular filling in early diastole, and these abnormalities persist during short and medium term follow-up.9 These fmdings may partly account for the depressingly high perioperative mortality still reported in centres with extensive experience. Review of surgical results suggests that children with a double-inlet left ventricle have a higher mortality than do those with tricuspid atresia, while an early mortality of 34% has been reported in patients in whom the systemic ventricle has right ventricular morphological features.10,11 Just as worrying are the results of longer term follow-up: there is a late hazard phase, with an increasing mortality at the start of the sixth postoperative year, usually related to "circulatory failure" .12 How can we improve on the operative results? First, since a low cardiac output as a result of reduced pulmonary flow is usually the cause of peroperative death, any means of augmenting output in this critical phase will have beneficial effects. No matter what type of surgical anastomosis is used, fenestration of the intra-atrial baffle, which increases systemic ventricular preload at the expense of arterial desaturation, is perhaps the greatest single advance in
development
the management of these patients.13 This procedure has led to a striking improvement in the immediate postoperative course, such that survival can now be expected even in patients previously thought to be at high risk. Subsequently, the fenestration can be easily closed, if necessary, by an umbrella or clamshell device inserted via a catheter. 14 A second area offering scope for improvement concerns flow of blood to the lungs. Positive pressure ventilation has a predictably deleterious effect on the flow of blood into the lungs, yet most postoperative regimens use this approach. Negative extrathoracic pressure ventilation could, by obviating the deleterious effects of positive pressure ventilation as well as by augmenting systemic venous return, be beneficial. The use of such a technique has been explored by Penny et al. 15 Early data suggest that this can double the flow of blood to the lungs (and hence cardiac output). A third possibility for improvement lies in the surgical procedure itself. Bypassing the right atrium, by use of a total has theoretical connection, cavopulmonary over the standard Fontan procedure.16 advantages Balaji et al 17 found that the frequency of arrhythmias was lower in patients after construction of a total cavopulmonary connection than after the Fontan operation, although follow-up in this study was short. These researchers also reported a lower mortality in the patients who underwent total cavopulmonary connection, although the post-Fontan mortality in their centre was very high (15% vs 34%). We now need to improve our understanding of the physiology of the Fontan circulation and determine how it can be manipulated, especially in the early postoperative period. Longer periods of follow-up will clarify the relative merits of the various modifications of the Fontan procedure, and show whether they have clear advantages over the original
approach. 1. Fontan S, Baudet E. Surgical repair of tricuspid atresia. Thorax 1971; 26: 240-48. 2. DeLeon SY, Ilbawi MN, Idriss SS, et al. Fontan-type operation for complex lesions. J Thorac Cardiovasc Surg 1986; 92: 1029-37. 3. Sullivan ID, Taylor JFN. Hearts with one ventricle: current concepts in management. Arch Dis Child 1989; 64: 166-71. 4. Choussat A, Fontan S, Vesse P, Vallot F, Chauve A, Bricaud H. Selection criteria for Fontan’s procedure. In: Anderson RH, Shinebourne EA, eds. Paediatric cardiology. Edinburgh: Churchill Livingstone, 1977: 559-66. 5. Fontan S, Fernandez G, Ebner A. Risk factors for the Fontan procedure. In: Crupi G, Parenzan L, Anderson RH, eds. Perspectives in pediatric cardiology. New York: Futura, 1989: 183-263. 6. Kirkland JK, Blackstone EH, Kirkland JW, Pacifico AD, Bargeron LM. The Fontan operation: ventricular hypertrophy, age and date of operation as risk factors. J Thorac Cardiovasc Surg 1986; 92: 1049-64. 7. Redington AN, Knight B, Oldershaw PJ, Shinebourne EA, Rigby ML. Left ventricular function in double inlet left ventricle before the Fontan operation: comparison with tricuspid atresia. Br Heart J 1988; 60: 324-31. 8. Penny DJ, Lincoln C, Shore DF, Xiao HB, Rigby ML, Redington AN. The early response of the systemic ventricle during transition to the
Fontan circulation: an acute hypertrophic cardiomyopathy? Cardiology in the Young 1992; 2: 78-84. 9. Penny DJ, Rigby ML, Redington AN. Abnormal patterns of intraventricular flow and diastolic filling after the Fontan operation: evidence for incoordinate ventricular wall motion. Br Heart J 1991; 66: 375-78.
1452
10. Coles JG, Kielmanowicz S, Freedom EM, et al. Surgical experience with the modified Fontan procedure. Circulation 1987; 76 (suppl): 61-66. 11. Matsuda H, Kawashima Y, Tishimoto H, et al. Problems in the modified Fontan operation for univentricular heart of the right ventricular type. Circulation 1987; 76 (suppl): 45-52. 12. Fontan S, Kirkland JW, Fernandez G, et al. Outcome after a "perfect" Fontan operation. Circulation 1990; 81: 1520-36. 13. Laks H, Pearl JM, Hass GS, et al. Partial Fontan: advantages of an adjustable interatrial communication. Ann Thorac Surg 1991; 52: 1084-95. 14. Bridges ND, Lock JE, Castineda AR. Baffle fenestration with subsequent transcatheter closure. Circulation 1990; 82: 1681-89. 15. Penny DJ, Hayek Z, Rawle P, Rigby ML, Redington AN. Ventilation with external high-frequency oscillation around a negative baseline increases pulmonary blood flow after the Fontan operation. Cardiology in the Young 1992; 2: 277-80. 16. DeLaval MR, Kilner P, Gewillig M, Bull C. Total cavopulmonary connection: a logical alternative to atrial pulmonary connection for complex Fontan operations. J Thorac Cardiovasc Surg 1988; 96: 682-95. 17. Balaji S, Gewellig M, Bull C, DeLeval MR, Deanfield JE. Arrhythmia after the Fontan procedure: comparison of total cavopulmonary connection and atriopulmonary connection. Circulation 1991; 84 (suppl): 162-66.
Medicinal Euroadvertising for 1993 Readers of the London edition of The Lancet who peruse the journal to the very last page will have noticed a strongly worded statement that requires advertisers to observe the provisions of, among other pieces of legislation, the Medicines Act 1968. But from Jan 1, 1993, the legally enforceable regulations that cover advertisements will be substantially strengthened and extended by European Community Council Directive 92/28/EEC (see Lancet Feb 22, p 483), which intends to set minimum standards on the advertising of medicinal products for human use throughout the Community. What will this new law mean for pharmaceutical companies and medical journals, and what responsibilities will it place on the doctor in his or her dealings with company
representatives? An example of how this EC directive might work is provided in the latest issue of the Drug and Therapeutics Bulletin.1 Etidronate (Didronel PMO, Norwich Eaton) is a bisphosphonate that is licensed in the UK for treatment of vertebral osteoporosis only. Yet, in advertising material that was sent to doctors in the UK earlier this year, the company answer their own question "who do I treat with Didronel PMO?" thus: "Postmenopausal women currently being treated for established osteoporosis; postmenopausal women with vertebral, wrist, or hip fractures due to osteoporosis; postmenopausal women who have X-ray evidence of osteoporosis; patients with clear signs and symptoms of established vertebral osteoporosis" (our italics). Only in the abbreviated prescribing information (in considerably smaller print) does the advertisement make clear that vertebral osteoporosis is the sole licensed indication. Such questionable claims could fall foul of the new EC directive.
existing British legislation,2 an advertisement is legal provided it is "not inconsistent with the particulars contained in the data sheet". The According
ruling is more definite: "All parts of the advertising... must comply with the particulars listed in the summary of product characteristics". The
new
EC
advertisement must go no further than the data sheet in its content. If an advertisement is deemed to exceed the licensed indications for a particular drug, the 1993 EC directive will allow member states to "confer upon the courts or administrative authorities powers to require in addition the enabling them publication of a corrective statement". For Didronel PMO, if the advertisement had appeared next year and legislation had been enacted, would this mean a press statement; a formal retraction in a subsequent advertisement; or an obligation on medical journals ...
publish a "corrective statement"? Since advertisements will be subject to legally enforceable modification and can rapidly become out of date, "any documentation relating to a medicinal product ... shall state the date on which it was drawn up or last revised". Two other important issues are addressed in the EC directive. First, doctors will not be allowed to "solicit or accept any inducement" from a drug company to prescribe or supply a medicinal product. Guidelines exist, such as those from the Association of the British Pharmaceutical Industry, about what company representatives are allowed to offer as inducements, but EC law will place a direct responsibility on doctors to refuse "gifts, pecuniary advantages, or benefits in kind ... unless they are inexpensive and relevant to the practice of medicine or pharmacy". Furthermore, in the UK Pharmaceutical Price Regulation Scheme, companies have been allowed to differentiate between "sales promotion" and "information expenses" (education). Since limits exist on the amount of money that can be spent on promotion, educational activities (eg, sponsored international meetings for which all expenses are paid for by the company) have allowed the industry to offer inducements that can be budgeted for under information expenses. This accountancy ruse will be prevented under the new EC directive. Advertising "shall include in particular... sponsorship of promotional meetings ... sponsorship of scientific congresses... and payment of their travelling and accommodation expenses". The rationalisation of expenditure into a single category, with most of the promotion and education budget being classed as advertising, will severely limit the amount of money that can be spent on inducements to to
prescribe. The directive is littered with "shall" and "may" but places on the twelve EC countries an obligation to set up schemes to monitor advertising. Prior vetting is one way; many journals (including The Lancet) do this now editorially, and, at an official level that is what France practises.
to
1. Etidronate for vertebral osteoporosis after the menopause. Drug Ther Bull 1992; 30: 45-46. 2. The Medicines Act 1968. London: HM Stationery Office, 1968.
