- Email: [email protected]
Management of Fallot's Tetralogy
305
right-ventricular outflow can evolve after birth and become progressively more severe. Some babies, initially free from cyanosis and thought to have only a large V.S.D., may over the first few months or years of life become increasingly cyanosed and clinically indistinguishable from those born with a more fully developed clinical picture. In such patients, too, management is complicated by the fact that the obstruction, being largely muscular, is often more dynamic than in those born with a narrow rudimentary outflow tract, and changes therein may play a part in the hypoxic spells or turns that often characterise the tetralogy. In the series of STARR and his colleagues,4for example, 15 of the 54 infants had little or no cyanosis and normal arterial saturation at rest (one actually had a left-to-right shunt). 14 of the to
THE LANCET
Management of Fallot’s Tetralogy THE story of Fallot’s tetralogy, as it has unfolded since TAUSSIG realised that an artificial ductus would palliate the symptoms of patients with severe central is almost the story of cardiac surgery itself. cyanosis,1-4 of its total correction in infancy are the Reports latest in a long series of advances that have transformed the outlook for those born with serious cardiac malformations. Yet there is still diversity of opinion about to which patients this diagnostic label should be attached-a Fallot in one clinic is not necessarily the same type of patient as a Fallot in another clinic, and such terms as acyanotic Fallot and pink tetralogy have added confusion to an already complex situation and made it difficult to compare published series. Obviously, the combination of a defect in the interventricular septum with obstruction to right-ventricular outflow can produce a wide range of clinical and hsmodynamic features, depending not only upon the absolute severity of the malformations themselves but also upon their severity relative to each other. Thus, a patient with a small ventricular septal defect (v.s.D.) and severe pulmonary stenosis is in no way similar to one with a large v.s.D. and modest infundibular obstruction. What FALLOT described was a fairly specific combination of these lesions that is almost certainly caused by malformation of the developing infundibulum-namely, a large anteriorly situated defect high in the interventricular septum, just beneath and approximately the same size as the aortic valve, which had maintained fibrous continuity with the aortic cusp of the mitral valve. This was combined with obstruction to right-ventricular outflow, in part or wholly infundibular, severe enough to produce similar peak pressures in the two ventricles. With this definition one might think it relatively easy to select a fairly homogeneous group who could be described as having tetralogy of Fallot; and with schoolchildren and adolescents this is so. But with infants and small children the clinical picture may change, often with surprising rapidity: obstruction 1. 2.
3. 4.
Barratt-Boyes, B. G., Simpson, M., Neutze, J. M. Circulation, 1971, 43, 25. Cartmill, T. B., Barr, P., Overton, J. H., Celermajer, J. M. Abstr. V Asian-Pacific Congr. Cardiol. 1972, 20. O’Brien, M. F. ibid. 19. Starr, A., Bonchek, L. I., Sutherland, C. O. J. thorac. cardiovasc. Surg. 1973, 65, 45.
25 who had total correction came from this group, and 10 of them were operated on before their first birthday. All are said to have had severe episodes of hypoxia that were not controlled by beta-blocker and to have had definite muscular infundibular stenosis with an adequate pulmonary annulus and pulmonary artery-precisely the type of patients that ERIKSSON and his co-workers5 have described as likely to respond satisfactorily to long-term propranolol therapy. Obviously, in these very young patients one is dealing with a changing situation in which management is less clearcut than it is in older children with more typical clinical features. Any group operated on in infancy will almost certainly contain a varying proportion of such cases, which, although they are probably going to become Fallotlike, should be included in the series only as a clearly defined subgroup, as they are in the Portland series.4 For the rest, with more classical tetralogy of Fallot, the situation is less confusing. Fallot’s is one of the commonest congenital cardiac malformations causing severe central cyanosis, and in presurgical times one of the few that allowed survival past infancy. Until the reports of its total correction in infancy, ideas about management were beginning to reach a consensus-so much so that in 1970 KIRKLIN and KARP introduced their bookwith the words, "The decision to create this monograph was based on the belief that surgery for the tetralogy of Fallot is now safe and reproducible. It is therefore teachable." Radical surgical treatment is necessary, because by and large the right ventricle will not function efficiently under a systemic work-load for more than a few years. Without treatment the most one can expect is survival into late adolescence or early adult life with severe and increasing physical handicap. In addition, several serious complications, such as stroke, cerebral abscess, and subacute bacterial endocarditis (S.B.E.), take their toll along the way. Palliative surgery, while lessening physical disability, does little 5. 6.
Eriksson, B. O., Thorén, C., Zetterqvist, P. Br. Heart J. 1969, 31, 37. Kirklin, J. W., Karp, R. B. The Tetralogy of Fallot from a Surgical Viewpoint. Philadelphia, 1970.
306
either to improve right-ventricular performance or to lessen the frequency of complications. In fact, one of the most striking findings of TAUSSIG’Slong-term follow-up of more than 700 of BLALOCK’s patients from Baltimore was that 5-5% of them had brain abscess with a 40% mortality, and no less than 14.3% had s.B.E. with a 21-4% mortality; in other words, those treated successfully had a 1-in-5 chance of
life-threatening sepsis. The surgery of the tetralogy is major surgery and, although excellent results can be achieved, it still carries a high potential morbidity and mortality. When should the operation be done ? And which type of operation-or more specifically, should definitive repair be preceded by one of the palliative procedures that increase blood-flow through the lungs ? In making recommendations, which are often of life and death, one must take into account the experience of the surgical team involved and the facilities available to them, rather than be guided by published results. Some groups s could report 100 consecutive total corrections in cyanosed patients over four years of age with a 7% mortality (the last 53 of them without a fatality) eight years ago; with others the mortality is still up to 20% for palliation, and around 10% is not uncommon.9,lOo Between 1945 and 1951, BLALOCK’s mortality in those under two years of age was 27-4%, but it was only 10% for the whole 728 cases. Between 1964 and 1972, STARR’S4 mortality in the 16 infants who had shunts created was 31%, but in the 25 who had total correction it was only 8%-figures that again emphasise the need to dissect out the details in published series before drawing conclusions about what to expect. The present position is that, ideally, complete intracardiac repair should be recommended to all patients. Where circumstances allow some choice of timing, it should be done between the ages of four and five years. Younger patients whose symptoms demand earlier surgical treatment should have a palliative operation, followed at a later stage by the definitive one.6,11 Patients seen for the first time when they are older should have palliative operations only if complete repair will carry a high risk of death. This applies also to adults: TRIMBLE et all have repaired 27 adult patients with a surgical mortality of 11 %, and BEACH et all 33 with a 9% mortality, most operative deaths being due to haemorrhage, a complication which is common in adults and due to excessive collateral circulation. Where palliative treatment has matters
Taussig, H. B. Johns Hopk. med. J. 1971, 129, 243, 258, 274. Malm, J. R., Blumenthal, S., Bowman, F. O., Jr., Ellis, K., Jameson, A. G., Jesse, M. J., Yeoh, C. B. J. thorac. cardiovasc. Surg. 1966, 52, 502. 9. Matthews, H. R., Belsey, R. H. R. Thorax, 1973, 28, 1. 10. Reid, J. M., Coleman, E. N., Barclay, R. S., Stevenson, J. G. ibid. p. 269. 11. Puga, F. J., Du Shane, J. W., McGoon, D. C. J. thorac. cardiovasc. Surg. 1972, 64, 247. 12. Trimble, A. S., Morch, J. E., Froggatt, M., Metni, F. N. Can. med. Ass. J. 1970, 103, 911. 13. Beach, P. M., Jr., Bowman, F. O., Jr., Kaiser, G. A., Malm, J. R. Circulation, 1971, 43, 37. 7. 8.
been satisfactory and the risks of complete repair seem likely to fall, operation may be deferred. In borderline cases the risks of naturally occurring complications have to be weighed against those of surgery. Results will continue to improve with experience. The pioneer Mayo Clinic group 14 reported that an early mortality of 28% in their first 74 patients had fallen to 16% in the last 25; and in Toronto 15 a mortality of 39% between 1957 and 1962 was down to 14% by 1966; so, if there is no urgency about repairing the malformations, it is probably best to wait. Of the palliative procedures, all have their proponents ; but anastomosis between the aorta and right pulmonary artery is a reasonable choice in the first year of life, while in older patients (because of the risk that too large a shunt may cause pulmonary hypertension) a subclavian to pulmonary artery anastomosis on the side opposite the aortic arch should relieve symptoms. For a time preliminary palliative operations were advocated in severe cases to increase pulmonary venous return and thus prepare the left heart for complete repair. Experience has shown that, although left-ventricular size may be an important consideration in infants and very small children, it is seldom inadequate after the age of four or five years of age. Conversely, a previous palliative operation has been suspected of prejudicing subsequent intracardiac repair. The effect of one upon the other has now been carefully investigated. One previous palliative operation does not seriously influence prognosis unless it has resulted in severe pulmonary vascular disease, in which case complete repair is contraindicated. Two or three previous palliative procedures increase the technical problems posed by complete repair and greatly increase the risk of operation. If an unsuccessful palliative procedure has resulted in obstruction to a pulmonary artery the risks of repair are considerable; and, depending on the size of the artery involved, those who survive the operation are less likely to have good long-term results. Complete repair should not be advised unless at least half the total pulmonary vascular bed is available for blood-flow.6 One group of patients requiring special treatment are those whose obstruction to right-ventricular outflow amounts to virtual or actual pulmonary atresia-the ultimate in severity so far as the tetralogy is concerned. The conduits and valves used in this situation seem to represent the last word in technical achievement.16-18 Some remarkable results have been obtained, but long-term prospects are clouded by early calcification in some of the newly created vascular channels. 14.
15. 16. 17. 18.
Kirklin, J. W., Ellis, F. H., Jr., McGoon, D. C., Du Shane, J. W., Swan, H. J. C. J. thorac. Surg. 1959, 37, 22. Goldman, B. S., Mustard, W. T., Trusler, G. S. Br. Heart J. 1968, 30, 563. Rastelli, G. C., Ongley, P. A., Davis, G. D., Kirklin, J. W. Mayo Clin. Proc. 1965, 40, 521. Ross, D. N., Somerville, J. Lancet, 1966, ii, 1446. McGoon, D. C. Curr. Probl. Surg. 1968, 3, 42.
307
Because most of the children born with serious cardiac malformations who do not survive die in the first few weeks or months of life, open-heart surgery in babies has not surprisingly become the highpriority technical challenge. In older children -the natural survivors-surgical treatment tends to be less urgent. Stimulated by the remarkable results from BARRATT-BOYES and his colleagues,! who reported that 33 of 37 infants under 10 kg. (25 of them aged eight days to twelve months) had survived intracardiac surgery under deep hypothermia with surface cooling and limited cardiopulmonary bypass, many centres are now
pursuing
a
much
more
aggressive
of surgery in infancy. 2-4,19, 20 The mortality is still somewhat high (up to 30% or more, and worst under the age of three months), but it will undoubtedly improve as it has for older children and adults during the past ten or fifteen years. The arguments for and against infant surgery are already beginning. Most babies with Fallot’s tetralogy are in no great danger in the neonatal period. Why take unnecessary risks when there is neither urgency nor even need to do so ?, say the conservatives: because, even if life is not threatened, early correction allows normal physical development throughout childhood and relieves the adverse effect of a severely handicapped child on the family situation, say the more adventurous. Obviously, if early correction is to become standard practice, it will have to achieve a lower mortality than either correction at a later stage or the combined mortality of early palliation followed by correction at a later stage. No judgment can yet be made; but if all the skills and resources can be concentrated in a relatively few specialist centres, so that intracardiac repair in babies does not become the next status symbol in cardiac surgery, there seems little doubt about the eventual outcome.
policy
Developments in Cystic Fibrosis Research ALTHOUGH cystic fibrosis (c.F.) has long been known to arise from the defect of an autosomal recessive gene (or genes), the identity of the defective gene(s) remains a complete mystery. Nor can any biochemical abnormality be regarded as primary, though ion transport, glycoprotein structure, and membrane permeability have all been under suspicion. A possible lead was the discovery, some years ago, of a humoral factor in cystics and heterozygotes which altered the motility of rabbit tracheal cilia and also inhibited the resorption of sodium in Breckenridge, I. M., Oelert, H., Graham, G. R., Stark, J., Waterston, D. J., Bonham-Carter, R. E. J. thorac. cardiovasc. Surg. 1973, 65, 58. 20. Malm, J. ibid. p. 64. 19.
in retrograde fashion.1,2 this factor was hampered by the nonquantitative nature of the ciliary effect and the technical difficulties of sodium-transport assay; but cilia from the gills of oysters and fresh-water mussels give With these tissues the a more quantitative assay. test measures cessation of ciliary motion (whereas the rabbit tracheal assay measures ciliary asynchrony); but seasonal variations in response are a difficulty.33 Despite the problems, information is emerging which may eventually lead to an understanding of the rat
parotid glands perfused
Work
on
pathogenesis ofc.F. Early attempts at fractionation on gel filtration columnssuggested that the anticiliary factor is adsorbed to several serum-proteins. BOWMAN’S group reported a consistent association of the factor with IgG-containing fractions4 and ScHMOYER et al.,5 by isoelectric focusing, showed that anticiliary activity is associated with several proteins of high isoelectric point.5 No pure sample has yet been obtained, but the factor is probably a low-molecularweight protein which tends to piggy-back " on other proteins, especially IgG during fractionation. CoNOVER et al. have now modified the original SPOCK assay for anticiliary activity and claim that their method reliably distinguishes normal control serum from that of heterozygotes and c.F. patients. (Since the test does not distinguish clearly between the heterozygote and homozygote, it is unlikely to be useful in antenatal screening.) In their investigation, all c.F. and heterozygote sera were positive, while 27 of the 29 normal subjects tested were negative.6 The same workers7 have observed anticiliary activity in the medium of lymphoid cell-lines cultured from c.F. patients and heterozygotes but not in that "
of cells cultured from control lines. Addition of the mitogen phytohxmagglutinin accelerated the rate of appearance of anticiliary factor in the c.F. and heterozygote lines, but control cell-lines remained negative. Addition of anti-human-IgG antiserum to the medium removed the anticiliary factor-which supports BOWMAN’S suggestion4 that the factor is bound to immunoglobulins in solution. These data are in general agreement with an extensive study by DANES et al.,8-10 who detected anticiliary activity, Spock, A., Heick, H. M. C., Cross, H., Logan, W. S. Pediat. Res. 1967, 1, 173. 2. Mangos, J., McSherry, N. ibid. 1967, 2, 378. 3. Besley, G. T., Patrick, A. D., Norman, A. P. J. med. Genet. 1969, 6, 278. 4. Bowman, B. H., Lockhart, L. H., McCombs, M. L. Science, 1970, 167, 871. 5. Schmoyer, I. R., Fischer, J. F., Brooks, S. P. Biochem. biophys. Res. Commun. 1972, 46, 1923. 6. Conover, J. H., Bonforte, R. J., Hathaway, P., Paciuc, S., Conod, E. J., Hirschhorn, K., Kopel, F. B. Pediat. Res. 1973, 7, 220. 7. Conover, J. H., Beratis, N. G., Conod, E. J., Ainbender, E., Hirschhorn, K. ibid. p. 224. 8. Danes, B. S., Beam, A. G. J. exp. Med. 1972, 136, 1313. 9. Bowman, B. H., Barnett, D. R., Matalon, R., Danes, B. S., Beam, A. G. Proc. natn. Acad. Sci. U.S.A. 1973, 70, 548. 10. Danes, B. S., Litwin, S. D., Hütteroth, T. H., Cleve, H., Bearn, A. G. J. exp. Med. 1973, 137, 1538. 1.
right-ventricular outflow can evolve after birth and become progressively more severe. Some babies, initially free from cyanosis and thought to have only a large V.S.D., may over the first few months or years of life become increasingly cyanosed and clinically indistinguishable from those born with a more fully developed clinical picture. In such patients, too, management is complicated by the fact that the obstruction, being largely muscular, is often more dynamic than in those born with a narrow rudimentary outflow tract, and changes therein may play a part in the hypoxic spells or turns that often characterise the tetralogy. In the series of STARR and his colleagues,4for example, 15 of the 54 infants had little or no cyanosis and normal arterial saturation at rest (one actually had a left-to-right shunt). 14 of the to
THE LANCET
Management of Fallot’s Tetralogy THE story of Fallot’s tetralogy, as it has unfolded since TAUSSIG realised that an artificial ductus would palliate the symptoms of patients with severe central is almost the story of cardiac surgery itself. cyanosis,1-4 of its total correction in infancy are the Reports latest in a long series of advances that have transformed the outlook for those born with serious cardiac malformations. Yet there is still diversity of opinion about to which patients this diagnostic label should be attached-a Fallot in one clinic is not necessarily the same type of patient as a Fallot in another clinic, and such terms as acyanotic Fallot and pink tetralogy have added confusion to an already complex situation and made it difficult to compare published series. Obviously, the combination of a defect in the interventricular septum with obstruction to right-ventricular outflow can produce a wide range of clinical and hsmodynamic features, depending not only upon the absolute severity of the malformations themselves but also upon their severity relative to each other. Thus, a patient with a small ventricular septal defect (v.s.D.) and severe pulmonary stenosis is in no way similar to one with a large v.s.D. and modest infundibular obstruction. What FALLOT described was a fairly specific combination of these lesions that is almost certainly caused by malformation of the developing infundibulum-namely, a large anteriorly situated defect high in the interventricular septum, just beneath and approximately the same size as the aortic valve, which had maintained fibrous continuity with the aortic cusp of the mitral valve. This was combined with obstruction to right-ventricular outflow, in part or wholly infundibular, severe enough to produce similar peak pressures in the two ventricles. With this definition one might think it relatively easy to select a fairly homogeneous group who could be described as having tetralogy of Fallot; and with schoolchildren and adolescents this is so. But with infants and small children the clinical picture may change, often with surprising rapidity: obstruction 1. 2.
3. 4.
Barratt-Boyes, B. G., Simpson, M., Neutze, J. M. Circulation, 1971, 43, 25. Cartmill, T. B., Barr, P., Overton, J. H., Celermajer, J. M. Abstr. V Asian-Pacific Congr. Cardiol. 1972, 20. O’Brien, M. F. ibid. 19. Starr, A., Bonchek, L. I., Sutherland, C. O. J. thorac. cardiovasc. Surg. 1973, 65, 45.
25 who had total correction came from this group, and 10 of them were operated on before their first birthday. All are said to have had severe episodes of hypoxia that were not controlled by beta-blocker and to have had definite muscular infundibular stenosis with an adequate pulmonary annulus and pulmonary artery-precisely the type of patients that ERIKSSON and his co-workers5 have described as likely to respond satisfactorily to long-term propranolol therapy. Obviously, in these very young patients one is dealing with a changing situation in which management is less clearcut than it is in older children with more typical clinical features. Any group operated on in infancy will almost certainly contain a varying proportion of such cases, which, although they are probably going to become Fallotlike, should be included in the series only as a clearly defined subgroup, as they are in the Portland series.4 For the rest, with more classical tetralogy of Fallot, the situation is less confusing. Fallot’s is one of the commonest congenital cardiac malformations causing severe central cyanosis, and in presurgical times one of the few that allowed survival past infancy. Until the reports of its total correction in infancy, ideas about management were beginning to reach a consensus-so much so that in 1970 KIRKLIN and KARP introduced their bookwith the words, "The decision to create this monograph was based on the belief that surgery for the tetralogy of Fallot is now safe and reproducible. It is therefore teachable." Radical surgical treatment is necessary, because by and large the right ventricle will not function efficiently under a systemic work-load for more than a few years. Without treatment the most one can expect is survival into late adolescence or early adult life with severe and increasing physical handicap. In addition, several serious complications, such as stroke, cerebral abscess, and subacute bacterial endocarditis (S.B.E.), take their toll along the way. Palliative surgery, while lessening physical disability, does little 5. 6.
Eriksson, B. O., Thorén, C., Zetterqvist, P. Br. Heart J. 1969, 31, 37. Kirklin, J. W., Karp, R. B. The Tetralogy of Fallot from a Surgical Viewpoint. Philadelphia, 1970.
306
either to improve right-ventricular performance or to lessen the frequency of complications. In fact, one of the most striking findings of TAUSSIG’Slong-term follow-up of more than 700 of BLALOCK’s patients from Baltimore was that 5-5% of them had brain abscess with a 40% mortality, and no less than 14.3% had s.B.E. with a 21-4% mortality; in other words, those treated successfully had a 1-in-5 chance of
life-threatening sepsis. The surgery of the tetralogy is major surgery and, although excellent results can be achieved, it still carries a high potential morbidity and mortality. When should the operation be done ? And which type of operation-or more specifically, should definitive repair be preceded by one of the palliative procedures that increase blood-flow through the lungs ? In making recommendations, which are often of life and death, one must take into account the experience of the surgical team involved and the facilities available to them, rather than be guided by published results. Some groups s could report 100 consecutive total corrections in cyanosed patients over four years of age with a 7% mortality (the last 53 of them without a fatality) eight years ago; with others the mortality is still up to 20% for palliation, and around 10% is not uncommon.9,lOo Between 1945 and 1951, BLALOCK’s mortality in those under two years of age was 27-4%, but it was only 10% for the whole 728 cases. Between 1964 and 1972, STARR’S4 mortality in the 16 infants who had shunts created was 31%, but in the 25 who had total correction it was only 8%-figures that again emphasise the need to dissect out the details in published series before drawing conclusions about what to expect. The present position is that, ideally, complete intracardiac repair should be recommended to all patients. Where circumstances allow some choice of timing, it should be done between the ages of four and five years. Younger patients whose symptoms demand earlier surgical treatment should have a palliative operation, followed at a later stage by the definitive one.6,11 Patients seen for the first time when they are older should have palliative operations only if complete repair will carry a high risk of death. This applies also to adults: TRIMBLE et all have repaired 27 adult patients with a surgical mortality of 11 %, and BEACH et all 33 with a 9% mortality, most operative deaths being due to haemorrhage, a complication which is common in adults and due to excessive collateral circulation. Where palliative treatment has matters
Taussig, H. B. Johns Hopk. med. J. 1971, 129, 243, 258, 274. Malm, J. R., Blumenthal, S., Bowman, F. O., Jr., Ellis, K., Jameson, A. G., Jesse, M. J., Yeoh, C. B. J. thorac. cardiovasc. Surg. 1966, 52, 502. 9. Matthews, H. R., Belsey, R. H. R. Thorax, 1973, 28, 1. 10. Reid, J. M., Coleman, E. N., Barclay, R. S., Stevenson, J. G. ibid. p. 269. 11. Puga, F. J., Du Shane, J. W., McGoon, D. C. J. thorac. cardiovasc. Surg. 1972, 64, 247. 12. Trimble, A. S., Morch, J. E., Froggatt, M., Metni, F. N. Can. med. Ass. J. 1970, 103, 911. 13. Beach, P. M., Jr., Bowman, F. O., Jr., Kaiser, G. A., Malm, J. R. Circulation, 1971, 43, 37. 7. 8.
been satisfactory and the risks of complete repair seem likely to fall, operation may be deferred. In borderline cases the risks of naturally occurring complications have to be weighed against those of surgery. Results will continue to improve with experience. The pioneer Mayo Clinic group 14 reported that an early mortality of 28% in their first 74 patients had fallen to 16% in the last 25; and in Toronto 15 a mortality of 39% between 1957 and 1962 was down to 14% by 1966; so, if there is no urgency about repairing the malformations, it is probably best to wait. Of the palliative procedures, all have their proponents ; but anastomosis between the aorta and right pulmonary artery is a reasonable choice in the first year of life, while in older patients (because of the risk that too large a shunt may cause pulmonary hypertension) a subclavian to pulmonary artery anastomosis on the side opposite the aortic arch should relieve symptoms. For a time preliminary palliative operations were advocated in severe cases to increase pulmonary venous return and thus prepare the left heart for complete repair. Experience has shown that, although left-ventricular size may be an important consideration in infants and very small children, it is seldom inadequate after the age of four or five years of age. Conversely, a previous palliative operation has been suspected of prejudicing subsequent intracardiac repair. The effect of one upon the other has now been carefully investigated. One previous palliative operation does not seriously influence prognosis unless it has resulted in severe pulmonary vascular disease, in which case complete repair is contraindicated. Two or three previous palliative procedures increase the technical problems posed by complete repair and greatly increase the risk of operation. If an unsuccessful palliative procedure has resulted in obstruction to a pulmonary artery the risks of repair are considerable; and, depending on the size of the artery involved, those who survive the operation are less likely to have good long-term results. Complete repair should not be advised unless at least half the total pulmonary vascular bed is available for blood-flow.6 One group of patients requiring special treatment are those whose obstruction to right-ventricular outflow amounts to virtual or actual pulmonary atresia-the ultimate in severity so far as the tetralogy is concerned. The conduits and valves used in this situation seem to represent the last word in technical achievement.16-18 Some remarkable results have been obtained, but long-term prospects are clouded by early calcification in some of the newly created vascular channels. 14.
15. 16. 17. 18.
Kirklin, J. W., Ellis, F. H., Jr., McGoon, D. C., Du Shane, J. W., Swan, H. J. C. J. thorac. Surg. 1959, 37, 22. Goldman, B. S., Mustard, W. T., Trusler, G. S. Br. Heart J. 1968, 30, 563. Rastelli, G. C., Ongley, P. A., Davis, G. D., Kirklin, J. W. Mayo Clin. Proc. 1965, 40, 521. Ross, D. N., Somerville, J. Lancet, 1966, ii, 1446. McGoon, D. C. Curr. Probl. Surg. 1968, 3, 42.
307
Because most of the children born with serious cardiac malformations who do not survive die in the first few weeks or months of life, open-heart surgery in babies has not surprisingly become the highpriority technical challenge. In older children -the natural survivors-surgical treatment tends to be less urgent. Stimulated by the remarkable results from BARRATT-BOYES and his colleagues,! who reported that 33 of 37 infants under 10 kg. (25 of them aged eight days to twelve months) had survived intracardiac surgery under deep hypothermia with surface cooling and limited cardiopulmonary bypass, many centres are now
pursuing
a
much
more
aggressive
of surgery in infancy. 2-4,19, 20 The mortality is still somewhat high (up to 30% or more, and worst under the age of three months), but it will undoubtedly improve as it has for older children and adults during the past ten or fifteen years. The arguments for and against infant surgery are already beginning. Most babies with Fallot’s tetralogy are in no great danger in the neonatal period. Why take unnecessary risks when there is neither urgency nor even need to do so ?, say the conservatives: because, even if life is not threatened, early correction allows normal physical development throughout childhood and relieves the adverse effect of a severely handicapped child on the family situation, say the more adventurous. Obviously, if early correction is to become standard practice, it will have to achieve a lower mortality than either correction at a later stage or the combined mortality of early palliation followed by correction at a later stage. No judgment can yet be made; but if all the skills and resources can be concentrated in a relatively few specialist centres, so that intracardiac repair in babies does not become the next status symbol in cardiac surgery, there seems little doubt about the eventual outcome.
policy
Developments in Cystic Fibrosis Research ALTHOUGH cystic fibrosis (c.F.) has long been known to arise from the defect of an autosomal recessive gene (or genes), the identity of the defective gene(s) remains a complete mystery. Nor can any biochemical abnormality be regarded as primary, though ion transport, glycoprotein structure, and membrane permeability have all been under suspicion. A possible lead was the discovery, some years ago, of a humoral factor in cystics and heterozygotes which altered the motility of rabbit tracheal cilia and also inhibited the resorption of sodium in Breckenridge, I. M., Oelert, H., Graham, G. R., Stark, J., Waterston, D. J., Bonham-Carter, R. E. J. thorac. cardiovasc. Surg. 1973, 65, 58. 20. Malm, J. ibid. p. 64. 19.
in retrograde fashion.1,2 this factor was hampered by the nonquantitative nature of the ciliary effect and the technical difficulties of sodium-transport assay; but cilia from the gills of oysters and fresh-water mussels give With these tissues the a more quantitative assay. test measures cessation of ciliary motion (whereas the rabbit tracheal assay measures ciliary asynchrony); but seasonal variations in response are a difficulty.33 Despite the problems, information is emerging which may eventually lead to an understanding of the rat
parotid glands perfused
Work
on
pathogenesis ofc.F. Early attempts at fractionation on gel filtration columnssuggested that the anticiliary factor is adsorbed to several serum-proteins. BOWMAN’S group reported a consistent association of the factor with IgG-containing fractions4 and ScHMOYER et al.,5 by isoelectric focusing, showed that anticiliary activity is associated with several proteins of high isoelectric point.5 No pure sample has yet been obtained, but the factor is probably a low-molecularweight protein which tends to piggy-back " on other proteins, especially IgG during fractionation. CoNOVER et al. have now modified the original SPOCK assay for anticiliary activity and claim that their method reliably distinguishes normal control serum from that of heterozygotes and c.F. patients. (Since the test does not distinguish clearly between the heterozygote and homozygote, it is unlikely to be useful in antenatal screening.) In their investigation, all c.F. and heterozygote sera were positive, while 27 of the 29 normal subjects tested were negative.6 The same workers7 have observed anticiliary activity in the medium of lymphoid cell-lines cultured from c.F. patients and heterozygotes but not in that "
of cells cultured from control lines. Addition of the mitogen phytohxmagglutinin accelerated the rate of appearance of anticiliary factor in the c.F. and heterozygote lines, but control cell-lines remained negative. Addition of anti-human-IgG antiserum to the medium removed the anticiliary factor-which supports BOWMAN’S suggestion4 that the factor is bound to immunoglobulins in solution. These data are in general agreement with an extensive study by DANES et al.,8-10 who detected anticiliary activity, Spock, A., Heick, H. M. C., Cross, H., Logan, W. S. Pediat. Res. 1967, 1, 173. 2. Mangos, J., McSherry, N. ibid. 1967, 2, 378. 3. Besley, G. T., Patrick, A. D., Norman, A. P. J. med. Genet. 1969, 6, 278. 4. Bowman, B. H., Lockhart, L. H., McCombs, M. L. Science, 1970, 167, 871. 5. Schmoyer, I. R., Fischer, J. F., Brooks, S. P. Biochem. biophys. Res. Commun. 1972, 46, 1923. 6. Conover, J. H., Bonforte, R. J., Hathaway, P., Paciuc, S., Conod, E. J., Hirschhorn, K., Kopel, F. B. Pediat. Res. 1973, 7, 220. 7. Conover, J. H., Beratis, N. G., Conod, E. J., Ainbender, E., Hirschhorn, K. ibid. p. 224. 8. Danes, B. S., Beam, A. G. J. exp. Med. 1972, 136, 1313. 9. Bowman, B. H., Barnett, D. R., Matalon, R., Danes, B. S., Beam, A. G. Proc. natn. Acad. Sci. U.S.A. 1973, 70, 548. 10. Danes, B. S., Litwin, S. D., Hütteroth, T. H., Cleve, H., Bearn, A. G. J. exp. Med. 1973, 137, 1538. 1.