- Email: [email protected]
Delayed Closure of the Ductus
436
evidence for the presence of HPV 5 in lesions. Now they have been able to demonstrate HPV 5 DNA in the malignant tissue from one of the patients with skin cancers. The parallels with EV are obvious but here the co-factors (pharmacological immunosuppression and UV irradiation) required for expression of the oncogenic potential of HPV 5 are more clearly defined. The idea that a virus may be just one of several influences contributing to the evolution of malignant disease is completely in line with current understanding of the multifactorial causation of cancer and, in the context of papillomaviruses, it is supported by observations in various animal tumours (cited by Lutzner and colleagues). In certain circumstances two unrelated viruses may be implicated where neither is sufficient, on its own, to cause a tumour. H. Zur Hausen, whose laboratory at Freiburg has contributed much to our knowledge of the papillomaviruses, has developed this theme over the past three years in relation to carcinoma of the cervix. 14,15He argues that herpes simplex type II and HPV, both of which have been linked epidemiologically to genital cancer, can interact in a way that leads to overt malignancy. The latest information from this group is that one particular HPV, type 16, seems very closely associated with malignant lesions of the cervix, whereas types 6 and I1 are found in vulval and cervical condylomas that remain benign."I Events are moving rapidly on the HPV front. Inevitably there is talk of "vaccines to prevent cancer":I this may be premature but it is not altogether fanciful.’ Equally exciting and perhaps less distant is the prospect of extending DNA analysis of the different HPV subtypes until tropism for particular tissues and oncogenicity can be correlated with the presence of specific DNA sequences. 16 The papillomaviruses may be about to fulfil their most important role as a meeting-point for viral, chemical, and molecular biological approaches to the understanding of human
viously detected immunological
cancer.
Delayed Closure of the Ductus IN fetal life the ductus arteriosus, a short wide vessel between the main pulmonary artery and the descending aorta, allows desaturated’blood from the upper body to pass via the superior vena cava and right ventricle to the umbilical arteries and placenta, thus bypassing the lungs. It normally closes soon after birth but occasionally it is abnormal and remains patent; to avoid the later complications of heart failure, pulmonary vascular disease, and bacterial endocarditis, surgical closure is recommended. This 14. Zur Hausen, H. The role of viruses in human tumours. Adv Cancer Res 1980; 33: 77-107. 15. Zur Hausen H. Human genital cancer: synergism between two virus infections or synergism and initiating events? Lancet 1982; ii: 1370-72. 16. Campo MS. Warts and all. Nature 1982; 298: 605-06.
condition, patent ductus arteriosus (PDA), has been recognised for many years but problems due to delayed closure of the normal ductus have only recently been described. They were not mentioned in textbooks of neonatal medicine before 1970 but are now a major preoccupation of those concerned with intensive care of the newborn. This reflects the improved survival of the very preterm infant and the increased use of mechanical ventilation; for delayed closure of the ductus is confined to the preterm infant. In utero, relative hypoxia and duct-produced prostaglandin E maintain duct patency-closure occurs soon after birth when the duct muscle constricts in response to a high arterial oxygen tension. In the preterm infant the ductus is large (in the most immature infants it may be larger than the aorta), the duct muscle is thin, and failure of the lungs to expand at birth and secondary atelectasis often prevent the infant from maintaining a rise in arterial p02, so the ductus remains open. Although often referred to as a PDA, the designation delayed closure of the ductus (DCD) is more precise. DCD is important because it allows shunting from the systemic to the pulmonary circulation, a reversal of what happens in utero. Thus, as the lung disorder resolves, the pulmonary vascular resistance drops and flow of blood from aorta to pulmonary artery increases, at times becoming torrential. Shunting occurs throughout the cardiac cycle; in fact, doppler studies have shown that, during diastole, flow in the descending aorta reverses and the ductus "steals" blood from the lower body.’ Retrograde flow in the mesenteric arteries in diastole may account for the susceptibility of affected infants to necrotising enterocolitis.2 Similar retrograde flow has been described in the anterior cerebral arteries, suggesting a cerebral steal.3 This requires confirmation since intracranial doppler flow studies in the newborn can be misinterpreted.4 A small shunt causes no problems, but as it gets larger it leads to apnoeic attacks, increasing respiratory difficulty, and ventilator dependence with a demand for a high inspired oxygen concentration and minute ventilation. With these comes an increased risk of chronic lung disease
(bronchopulmonary dysplasia). According to a US collaborative study,5 the clinical features of DCD most helpful in diagnosis are an increasing need for respiratory support, collapsing pulses, an easily palpable cardiac impulse, and a murmur. Depending on the pulmonary dynamics GA, Armstrong BE, Anderson PAW. Noninvasive detection of retrograde descending aortic flow in infants using continuous wave Doppler ultrasonography J Pediatr 1980; 97: 394-400. Bell EF, Warburton D, Stonestreet BS, Oh W. Effect of fluid administration on the development of symptomatic patent ductus arteriosus and congestive heart failure in premature infants. N EnglJ Med 1980; 302: 598-604. Lipman B, Serwer GA, Brazy JE. Abnormal cerebral haemodynamics in preterm
1. Serwer
2.
3. 4. 5.
infants with patent ductus arteriosus. Paediatrics 1982; 69: 818-22. Bejar R, Merritt TA, Coen RW, Manning F, Gluck L. Pulsatility index, patent ductus arteriosus, and brain damage. Pediatrics 1982, 69: 818-22. Ellison RC, Peckham GJ, Lang P, Talner NS, Lerer TJ, Lin L, Dooley KJ, Nadas AS. Evaluation of the preterm infant for patent ductus 364-72.
arteriosus.
Pediatrics 1983; 71:
437
which control the size of the shunt, the murmur may be continuous, systolic only, or (occasionally) absent. An enlarged left atrium on the echocardiogram (left atrial to aortic root ratio of I - 15 or more) is commonly found, but it is less specific. The chest X-ray usually shows cardiac enlargement with pulmonary plethora or oedema, but it may be difficult to interpret in the presence of pre-existing lung disease. Two other investigations look promising. Doppler detection of retrograde diastolic blood-flow in the descending aorta may be useful not only in diagnosis but also for measuring the size of the shunt;6 however, the equipment is not yet in routine use. Real-time echocardiography with a high-frequency (7’5 mHz) probe in the suprasternal view will display the ductus itself (rather than the shunt), but the technique requires much skill.7 How should a preterm infant with DCD be managed? Small ducts with no symptoms should be left alone for they usually close spontaneously by the infant’s expected date of delivery. The usual treatment for a haemodynamically significant ductus is reduction of the infant’s fluid intake (to 100-120 ml/kg per day), correction of anaemia, and the administration of a diuretic. Frusemide (1-2 mg/kg per day) is effective and widely used; but there has been a worrying report that it may promote the development of DCD in infants with respiratory distress syndrome (RDS). In a US study, frusemide was compared with a thiazide diuretic in infants who had RDS and no evidence of a ductus (the reason why a diuretic was given is not made clear). Signs of DCD developed in 16 of 33 frusemidetreated infants compared with 8 of 33 chlorothiazidetreated infants-a significant difference. Frusemide was found to increase urinary prostaglandin excretion, suggesting that the increased incidence of DCD was due to higher renal synthesis of prostaglandin E, a potent smooth-muscle dilator. The frusemide-treated infants, however, had a rather lower mortality and morbidity, perhaps because the beneficial effects outweighed the effects of a ductus. No study has shown that frusemide given to infants with signs of a ductus will delay closure. Digoxin is not to be recommended, since preterm infants are easily overdosed and it is very unlikely to improve the function of an already vigorously contracting left ventricle. If this supportive treatment is not effective, an attempt at "medical closure" with the anti-prostaglandin indomethacin is the next step. Great caution was recommended when this approach was introduced ("don’t rush to the drugstore yet")9 but numerous studies have since 6. Serwer
GA, Armstrong BE, Anderson PAW. Continuous wave Doppler ultrasonographic quantitation of patent ductus arteriosus flow. J Pediatr 1982; 100:
297-99 7 Smallhorn JF, Huhta
JC, Anderson RH, Macartney FJ. Suprasternal cross-sectional echocardiography in assessment of patent ductus arteriosus. Br Heart J1982; 48:
shown it
be safe and effective. Two or three doses mg/kg each) at intervals of 12-24 h are probably necessary to close the ductus and "nail it shut". 10 The intravenous route seems rather more effective and carries less risk of gastric haemorrhage than does the oral route. Transient oliguria with dilutional hyponatraemia results from the direct action of indomethacin on the renal tubule and can be prevented by fluid restriction or the simultaneous administration of frusemide.11 It is encouraging that the concurrent use of frusemide does not seem to inhibit duct closure. Thrombocytopenia (platelet count below 75 000/1), a bilirubin approaching exchange-transfusion levels, and necrotising enterocolitis are contraindications to the use of indomethacin. Duct-closure rates of 80-90% have been reported in indomethacin-treated infants 12 although rates are lower in infants over two weeks old. 13I In a recent double blind trial of indomethacin versus fluid restriction alone,’4 the initial success rate with indomethacin was high (87% duct closure) but in almost half the responders the ductus reopened within the next two weeks. The relapse rate was exceptionally high in infants weighing less than 1000 g. Many of the infants in this study were given only one or two doses and it would be interesting to know what the relapse rate would have been after three doses. The encouraging finding was that the reopened ductuses usually closed spontaneously and surgery was not
required. Infants with a symptomatic ductus who fail to respond to indomethacin or who respond and then relapse with the reappearance of symptoms need surgical closure. They require the skills of either a cardiac surgeon with experience of infants or a paediatric surgeon familiar with chest surgery in the newborn. In the UK such surgeons often do not work in the hospital providing neonatal intensive care. The easiest and safest solution will usually be for the surgeon to visit the infant to operate rather than to transport the infant to the surgeon. Accurate anatomical definition of the ductus is important. In preterm infants it is large and may be confused with the aorta itself. To avoid ligation of the wrong artery it is helpful to listen to the murmur with an oesophageal stethoscope at operation andI confirm that it disappears when the ductus is ligated. 15
10. Nadas AS. Indomethacin and the patent ductus arteriosus. N Engl J Med 1981; 305: 97-8. 11. Yeh TF, Wilks A, Singh J, Betkerur M, Lilien L, Pildes RS. Furosemide prevents the renal side-effects of indomethacin therapy in premature infants with patent ductus arteriosus J Pediatr 1982; 101: 433-37 12. Bhat R, Fisher E, Raju TNK, Vidyanagar D. Patent ductus arteriosus: recent advances in diagnosis and management. Pediatr Clins N Am 1982; 29: 1117-36. 13. Halliday HL, Hirata T, Brady JP. Indomethacin therapy for large patent ductus arteriosus in the
64: 154-59. 14 Rudd P, Montanez
321-30
Johnson DE, Lock JE. Furosemide promotes patent ductus premature infants with the respiratory distress syndrome. N Engl J Med 1983; 308: 743-48. 9 Nadas AS Patent ductus arteriosus revisited. N Engl J Med 1976; 295: 563-65.
low birth weight
infant: Results
and complications. Pediatrics 1979;
P, Hallidie-Smith K, Silverman M. Indomethacin
patent ductus arteriosus in very low birthweight infants
8 Green TP, Thompson TR, arteriosus in
to
(0’ 2
treatment for Double blind trial. Arch Dis
Childh 1983; 58: 267-70. 15.
Fleming WH, Sarafian LB, Kugler JD, Nelson RM. Ligation of patent ductus arteriosus in premature infants: Importance of accurate anatomic definition. Pediatrics 1983; 71: 373-75.
evidence for the presence of HPV 5 in lesions. Now they have been able to demonstrate HPV 5 DNA in the malignant tissue from one of the patients with skin cancers. The parallels with EV are obvious but here the co-factors (pharmacological immunosuppression and UV irradiation) required for expression of the oncogenic potential of HPV 5 are more clearly defined. The idea that a virus may be just one of several influences contributing to the evolution of malignant disease is completely in line with current understanding of the multifactorial causation of cancer and, in the context of papillomaviruses, it is supported by observations in various animal tumours (cited by Lutzner and colleagues). In certain circumstances two unrelated viruses may be implicated where neither is sufficient, on its own, to cause a tumour. H. Zur Hausen, whose laboratory at Freiburg has contributed much to our knowledge of the papillomaviruses, has developed this theme over the past three years in relation to carcinoma of the cervix. 14,15He argues that herpes simplex type II and HPV, both of which have been linked epidemiologically to genital cancer, can interact in a way that leads to overt malignancy. The latest information from this group is that one particular HPV, type 16, seems very closely associated with malignant lesions of the cervix, whereas types 6 and I1 are found in vulval and cervical condylomas that remain benign."I Events are moving rapidly on the HPV front. Inevitably there is talk of "vaccines to prevent cancer":I this may be premature but it is not altogether fanciful.’ Equally exciting and perhaps less distant is the prospect of extending DNA analysis of the different HPV subtypes until tropism for particular tissues and oncogenicity can be correlated with the presence of specific DNA sequences. 16 The papillomaviruses may be about to fulfil their most important role as a meeting-point for viral, chemical, and molecular biological approaches to the understanding of human
viously detected immunological
cancer.
Delayed Closure of the Ductus IN fetal life the ductus arteriosus, a short wide vessel between the main pulmonary artery and the descending aorta, allows desaturated’blood from the upper body to pass via the superior vena cava and right ventricle to the umbilical arteries and placenta, thus bypassing the lungs. It normally closes soon after birth but occasionally it is abnormal and remains patent; to avoid the later complications of heart failure, pulmonary vascular disease, and bacterial endocarditis, surgical closure is recommended. This 14. Zur Hausen, H. The role of viruses in human tumours. Adv Cancer Res 1980; 33: 77-107. 15. Zur Hausen H. Human genital cancer: synergism between two virus infections or synergism and initiating events? Lancet 1982; ii: 1370-72. 16. Campo MS. Warts and all. Nature 1982; 298: 605-06.
condition, patent ductus arteriosus (PDA), has been recognised for many years but problems due to delayed closure of the normal ductus have only recently been described. They were not mentioned in textbooks of neonatal medicine before 1970 but are now a major preoccupation of those concerned with intensive care of the newborn. This reflects the improved survival of the very preterm infant and the increased use of mechanical ventilation; for delayed closure of the ductus is confined to the preterm infant. In utero, relative hypoxia and duct-produced prostaglandin E maintain duct patency-closure occurs soon after birth when the duct muscle constricts in response to a high arterial oxygen tension. In the preterm infant the ductus is large (in the most immature infants it may be larger than the aorta), the duct muscle is thin, and failure of the lungs to expand at birth and secondary atelectasis often prevent the infant from maintaining a rise in arterial p02, so the ductus remains open. Although often referred to as a PDA, the designation delayed closure of the ductus (DCD) is more precise. DCD is important because it allows shunting from the systemic to the pulmonary circulation, a reversal of what happens in utero. Thus, as the lung disorder resolves, the pulmonary vascular resistance drops and flow of blood from aorta to pulmonary artery increases, at times becoming torrential. Shunting occurs throughout the cardiac cycle; in fact, doppler studies have shown that, during diastole, flow in the descending aorta reverses and the ductus "steals" blood from the lower body.’ Retrograde flow in the mesenteric arteries in diastole may account for the susceptibility of affected infants to necrotising enterocolitis.2 Similar retrograde flow has been described in the anterior cerebral arteries, suggesting a cerebral steal.3 This requires confirmation since intracranial doppler flow studies in the newborn can be misinterpreted.4 A small shunt causes no problems, but as it gets larger it leads to apnoeic attacks, increasing respiratory difficulty, and ventilator dependence with a demand for a high inspired oxygen concentration and minute ventilation. With these comes an increased risk of chronic lung disease
(bronchopulmonary dysplasia). According to a US collaborative study,5 the clinical features of DCD most helpful in diagnosis are an increasing need for respiratory support, collapsing pulses, an easily palpable cardiac impulse, and a murmur. Depending on the pulmonary dynamics GA, Armstrong BE, Anderson PAW. Noninvasive detection of retrograde descending aortic flow in infants using continuous wave Doppler ultrasonography J Pediatr 1980; 97: 394-400. Bell EF, Warburton D, Stonestreet BS, Oh W. Effect of fluid administration on the development of symptomatic patent ductus arteriosus and congestive heart failure in premature infants. N EnglJ Med 1980; 302: 598-604. Lipman B, Serwer GA, Brazy JE. Abnormal cerebral haemodynamics in preterm
1. Serwer
2.
3. 4. 5.
infants with patent ductus arteriosus. Paediatrics 1982; 69: 818-22. Bejar R, Merritt TA, Coen RW, Manning F, Gluck L. Pulsatility index, patent ductus arteriosus, and brain damage. Pediatrics 1982, 69: 818-22. Ellison RC, Peckham GJ, Lang P, Talner NS, Lerer TJ, Lin L, Dooley KJ, Nadas AS. Evaluation of the preterm infant for patent ductus 364-72.
arteriosus.
Pediatrics 1983; 71:
437
which control the size of the shunt, the murmur may be continuous, systolic only, or (occasionally) absent. An enlarged left atrium on the echocardiogram (left atrial to aortic root ratio of I - 15 or more) is commonly found, but it is less specific. The chest X-ray usually shows cardiac enlargement with pulmonary plethora or oedema, but it may be difficult to interpret in the presence of pre-existing lung disease. Two other investigations look promising. Doppler detection of retrograde diastolic blood-flow in the descending aorta may be useful not only in diagnosis but also for measuring the size of the shunt;6 however, the equipment is not yet in routine use. Real-time echocardiography with a high-frequency (7’5 mHz) probe in the suprasternal view will display the ductus itself (rather than the shunt), but the technique requires much skill.7 How should a preterm infant with DCD be managed? Small ducts with no symptoms should be left alone for they usually close spontaneously by the infant’s expected date of delivery. The usual treatment for a haemodynamically significant ductus is reduction of the infant’s fluid intake (to 100-120 ml/kg per day), correction of anaemia, and the administration of a diuretic. Frusemide (1-2 mg/kg per day) is effective and widely used; but there has been a worrying report that it may promote the development of DCD in infants with respiratory distress syndrome (RDS). In a US study, frusemide was compared with a thiazide diuretic in infants who had RDS and no evidence of a ductus (the reason why a diuretic was given is not made clear). Signs of DCD developed in 16 of 33 frusemidetreated infants compared with 8 of 33 chlorothiazidetreated infants-a significant difference. Frusemide was found to increase urinary prostaglandin excretion, suggesting that the increased incidence of DCD was due to higher renal synthesis of prostaglandin E, a potent smooth-muscle dilator. The frusemide-treated infants, however, had a rather lower mortality and morbidity, perhaps because the beneficial effects outweighed the effects of a ductus. No study has shown that frusemide given to infants with signs of a ductus will delay closure. Digoxin is not to be recommended, since preterm infants are easily overdosed and it is very unlikely to improve the function of an already vigorously contracting left ventricle. If this supportive treatment is not effective, an attempt at "medical closure" with the anti-prostaglandin indomethacin is the next step. Great caution was recommended when this approach was introduced ("don’t rush to the drugstore yet")9 but numerous studies have since 6. Serwer
GA, Armstrong BE, Anderson PAW. Continuous wave Doppler ultrasonographic quantitation of patent ductus arteriosus flow. J Pediatr 1982; 100:
297-99 7 Smallhorn JF, Huhta
JC, Anderson RH, Macartney FJ. Suprasternal cross-sectional echocardiography in assessment of patent ductus arteriosus. Br Heart J1982; 48:
shown it
be safe and effective. Two or three doses mg/kg each) at intervals of 12-24 h are probably necessary to close the ductus and "nail it shut". 10 The intravenous route seems rather more effective and carries less risk of gastric haemorrhage than does the oral route. Transient oliguria with dilutional hyponatraemia results from the direct action of indomethacin on the renal tubule and can be prevented by fluid restriction or the simultaneous administration of frusemide.11 It is encouraging that the concurrent use of frusemide does not seem to inhibit duct closure. Thrombocytopenia (platelet count below 75 000/1), a bilirubin approaching exchange-transfusion levels, and necrotising enterocolitis are contraindications to the use of indomethacin. Duct-closure rates of 80-90% have been reported in indomethacin-treated infants 12 although rates are lower in infants over two weeks old. 13I In a recent double blind trial of indomethacin versus fluid restriction alone,’4 the initial success rate with indomethacin was high (87% duct closure) but in almost half the responders the ductus reopened within the next two weeks. The relapse rate was exceptionally high in infants weighing less than 1000 g. Many of the infants in this study were given only one or two doses and it would be interesting to know what the relapse rate would have been after three doses. The encouraging finding was that the reopened ductuses usually closed spontaneously and surgery was not
required. Infants with a symptomatic ductus who fail to respond to indomethacin or who respond and then relapse with the reappearance of symptoms need surgical closure. They require the skills of either a cardiac surgeon with experience of infants or a paediatric surgeon familiar with chest surgery in the newborn. In the UK such surgeons often do not work in the hospital providing neonatal intensive care. The easiest and safest solution will usually be for the surgeon to visit the infant to operate rather than to transport the infant to the surgeon. Accurate anatomical definition of the ductus is important. In preterm infants it is large and may be confused with the aorta itself. To avoid ligation of the wrong artery it is helpful to listen to the murmur with an oesophageal stethoscope at operation andI confirm that it disappears when the ductus is ligated. 15
10. Nadas AS. Indomethacin and the patent ductus arteriosus. N Engl J Med 1981; 305: 97-8. 11. Yeh TF, Wilks A, Singh J, Betkerur M, Lilien L, Pildes RS. Furosemide prevents the renal side-effects of indomethacin therapy in premature infants with patent ductus arteriosus J Pediatr 1982; 101: 433-37 12. Bhat R, Fisher E, Raju TNK, Vidyanagar D. Patent ductus arteriosus: recent advances in diagnosis and management. Pediatr Clins N Am 1982; 29: 1117-36. 13. Halliday HL, Hirata T, Brady JP. Indomethacin therapy for large patent ductus arteriosus in the
64: 154-59. 14 Rudd P, Montanez
321-30
Johnson DE, Lock JE. Furosemide promotes patent ductus premature infants with the respiratory distress syndrome. N Engl J Med 1983; 308: 743-48. 9 Nadas AS Patent ductus arteriosus revisited. N Engl J Med 1976; 295: 563-65.
low birth weight
infant: Results
and complications. Pediatrics 1979;
P, Hallidie-Smith K, Silverman M. Indomethacin
patent ductus arteriosus in very low birthweight infants
8 Green TP, Thompson TR, arteriosus in
to
(0’ 2
treatment for Double blind trial. Arch Dis
Childh 1983; 58: 267-70. 15.
Fleming WH, Sarafian LB, Kugler JD, Nelson RM. Ligation of patent ductus arteriosus in premature infants: Importance of accurate anatomic definition. Pediatrics 1983; 71: 373-75.