Arch Dis Child: first published as 10.1136/adc.59.10.966 on 1 October 1984. Downloaded from

Archives of Disease in Childhood, 1984, 59, 966-970

Unsuspected cardiopulmonary abnormalities complicating bronchopulmonary dysplasia

S H ABMAN, F J ACCURSO, AND C M BOWMAN Department of Paediatrics and Webb-Waring Lung Institute, University of Colorado School of Medicine, USA

SUMMARY Bronchopulmonary dysplasia is a serious chronic lung disease of infancy but despite numerous problems such as poor growth, recurrent lower respiratory tract infections, and cor pulmonale, steady improvement and recovery may generally be expected. We report four infants with bronchopulmonary dysplasia in whom the cardiopulmonary course did not show the usual steady improvement. Each infant was found to have an unsuspected cardiopulmonary lesion in addition to lung disease: two had congenital heart disease and two upper airway obstruction. Three improved after surgical intervention but one patient died immediately after this. Persistent right ventricular hypertrophy in patients with bronchopulmonary dysplasia maintained on supplemental oxygen, and a particularly slow rate of recovery from the need for supplemental oxygen are markers that should lead to evaluation for coexisting cardiopulmonary abnormalities. copyright.

Bronchopulmonary dysplasia is a chronic lung dis- difficult to recognise because they produce symp- ease of infancy characterised by persistent respira- toms similar to the underlying disease, and would tory distress and oxygen dependency after oxygen probably delay the patient's recovery. Furthermore, and ventilator management in the newborn period.1 such lesions might contribute to the pathophysiology

Mortality from bronchopulmonary dysplasia has of bronchopulmonary dysplasia by worsening hy- http://adc.bmj.com/ been reported to be 30 and 50% and most deaths poxaemia or increasing pulmonary blood flow and occur during the initial hospital admission.2 3 De- pressure. Because of the importance of diagnosing spite numerous problems such as poor growth, any complicating coexisting lesions we have begun recurrent respiratory infections, pulmonary hyper- to investigate more completely and invasively the tension, and cor pulmonale, steady improvement cardiopulmonary status of patients with bronchopul- and recovery may generally be expected with the monary dysplasia whose clinical status worsens or provision of appropriate care.4 improves very slowly.

The speed of recovery after the initial lung insult We report four infants with bronchopulmonary on September 28, 2021 by guest. Protected has been attributed to a balance between the dysplasia whose cardiorespiratory problems and severity of the underlying lung disease and the rate growth improved initially, but then plateaued or of lung growth and healing.2 Although lung function worsened. These four were found to have severe in patients with bronchopulmonary dysplasia unsuspected cardiopulmonary lesions in addition to generally im5proves, the rate of improvement may the lung disease. Each newly diagnosed problem vary widely. 6Parameters commonly used to assess was at least potentially treatable. We speculate that overall status include growth and development, early diagnosis of coexisting problems will hasten degree of respiratory distress, oxygen requirement, the patient's recovery. frequency of hospital admissions, and severity of cardiac disease-particularly right ventricular Case reports hypertrophy. Unfortunately, a variety of cardiac or pulmonary abnormalities could, if present, worsen a Case 1. A girl of 32 weeks' gestation and birthweight patient's status further and decrease the chance of 1630 g was intubated on day 1 for respiratory complete recovery. These 'hidden' lesions would be distress due to hyaline membrane disease. Her 966 Arch Dis Child: first published as 10.1136/adc.59.10.966 on 1 October 1984. Downloaded from

Unsuspected cardiopulmonary complications of BPD 967 respiratory status improved over the first 72 hours but required digoxin for treatment of right heart but then worsened because of a patent ductus failure due to presumed cor pulmonale secondary to arteriosus. Her symptoms resolved with diuretics bronchopulmonary dysplasia. She was lost to follow and fluid restriction. She was extubated, and on day up until 18 months of age when she was brought to 12 was transferred to a community hospital. Her the local clinic for treatment of otitis media, chest radiograph showed small cystic lesions com- conjunctivitis, and facial cellulitis. At that time her patible with the early stages of bronchopulmonary weight was well below the fifth centile, she had a dysplasia, her electrocardiogram showed right ven- noticeably increased second heart sound without tricular hypertrophy and a raised right systolic time murmur or gallop, her electrocardiograph showed interval (0.43) but no anatomic abnormalities were right ventricular hypertrophy, and chest radiograph found on echocardiogram. After two months she showed a large heart with diffuse bilateral infil- was discharged home, requiring about three litres trates. She was admitted for treatment of her facial oxygen per minute by nasal cannula to maintain a cellulitis with parenteral antibiotics and was later Po2 of 7*3 kPa (55 mm Hg). Over the next seven transferred to our hospital for evaluation and months she grew poorly, had a minimal reduction in treatment of her severe hypoxaemia and congestive oxygen requirements, and suffered recurrent epi- heart failure. On arrival, her transcutaneous Po2 in sodes of respiratory distress. At 10 months of age room air was 3-9 kPa (29 mm Hg). Her echocardio- she was admitted to hospital for cardiac catheterisa- gram showed a large patent ductus arteriosus, tion because of clinical and electrocardiographic prolonged right systolic time interval (0-40), and left evidence of persistent pulmonary hypertension. ventricular dysfunction. Cardiac catheterisation Physical examination showed a small thin child showed left to right shunting through an atrial septal whose length and weight were less than the fifth defect, bidirectional shunting through a ventricular centile for corrected age and who had mild respira- septal defect, and right to left shunting through a tory distress, a respiratory rate of 60, and scattered patent ductus arterious. In addition, she had an rales bilaterally. She had tachycardia and a grade interrupted aortic arch between the left carotid and

I/VI systolic murmur without gallop. The second subclavian arteries and severe pulmonary hyperten- copyright. heart sound was noticeably increased-most sion with a pulmonary artery pressure of 90 mm Hg. prominently in the pulmonary area. She did not have She underwent cardiac surgery for ligation of the an active precordium or bounding pulses. There was patent ductus arteriosus and correction of the no hepatomegaly or peripheral oedema. An electro- interrupted arch. A lung biopsy taken during the cardiograph showed right ventricular hypertrophy surgery showed moderate hypertrophy of the arter- but no evidence of left atrial enlargement. A right iolar media and noticeable intimal proliferation, systolic time interval of 0-40 was found on echocar- with early fibrosis within the proliferating intima

diogram. Her Po2 was 4-4 kPa (33 mm Hg) when she consistent with grade III Heath-Edwards changes. http://adc.bmj.com/ breathed room air and 7.9 kPa (60 mm Hg) on two Occlusion of medium sized arteries and mild alveo- litres of oxygen per minute by nasal cannula. lar septal fibrosis were noted. On the second day Cardiac catheterisation showed an atrial septal after operation, and despite mechanical ventilation, defect, patent ductus arteriosus, and pulmonary she died from a cardiac arrest secondary to severe hypertension, with a mean pulmonary artery press- hypoxia. ure of 27 mm Hg on four litres of oxygen delivered by face mask. Left to right shunting through the Case 3. A boy of 27 weeks' gestation and birth- ductus and atrial septal defect was noted. After weight 1015 g required intubation in the delivery on September 28, 2021 by guest. Protected closure of her patent ductus arteriosus and atrial room for severe respiratory distress. His initial septal defect she has shown steady but slow im- course and chest radiographs were consistent with provement in her room oxygenation, improved hyaline membrane disease. He subsequently de- growth, and resolution of the echocardiographic and veloped bronchopulmonary dysplasia and was not electrocardiographic evidence of right ventricular extubated until 48 days of age. His course was hypertrophy. She no longer needs supplemental further complicated by staphylococcal bacteraemia oxygen, but has continued to require diuretic and a candida urinary tract infection. He was treatment for three years. discharged at 3 months of age on half a litre of oxygen per minute by nasal cannula to maintain a Case 2. A girl born at 34 weeks' gestation and Po2 greater than 7-3 kPa (55 mm Hg) at all times. weighing 2400 g developed severe respiratory dis- He subsequently required multiple admissions to tress after delivery and required positive pressure hospital for lower respiratory tract infections and ventilation. After a long and complicated course she congestive heart failure. Because of poor growth was discharged from hospital without home oxygen, and persistent electrocardiographic findings of right Arch Dis Child: first published as 10.1136/adc.59.10.966 on 1 October 1984. Downloaded from

968 Abman, Accurso, and Bowman ventricular hypertrophy, he was admitted at 11/2 25 mm Hg when breathing high oxygen concentra- years of age for cardiac catheterisation to rule out tion (FIO2 greater than 0-80). No anatomic defects anatomic heart disease. Physical examination were found. After discharge, he still required showed length and weight below the fifth centile for frequent admissions for treatment of reactive air- corrected age, a grade II/VI systolic murmur at the ways disease. At 19 months of age, because of his left sternal border, and a loud second heart sound. frequent hospital admissions, poor growth, and Findings at catheterisation were severe pulmonary persistent echocardiographic evidence of right ven- hypertension with a pulmonary artery pressure of 88 tricular hypertrophy he underwent bronchoscopy. mm Hg when breathing room air (Pao2 4.7 kPa (35 This showed a subglottic cyst that extended to the mm Hg)) and no anatomic defects. Home oxygen carina and caused 40% obstruction of the airway. treatment was continued. He was readmitted at 21/2 Tracheostomy was performed. Since that time he years of age to evaluate possible upper airway has undergone further bronchoscopy for dilatation, obstruction because of recurrent otitis media and and resection of the subglottic lesion. His oxygen intermittent nocturnal coughing and snoring. requirement is slowly decreasing. Physical examination showed mouth breathing and bilateral intraorbital oedema with bluish discoloura- Results tion, his nasal mucosa seemed 'boggy' with watery rhinorrhea, and tonsillar hypertrophy was found. Breath sounds were clear. The second heart sound The Table summarises the clinical course, findings, was still increased. His room air TcPo2 fell from 5-6 treatment, and outcome of the four infants re- kPa (42 mm Hg) while awake to 3-9 kPa (30 mm Hg) ported. Each patient showed persistent evidence of while sleeping during episodes of snoring. Tonsillec- increased pulmonary pressures and right ventricular tomy and adenoidectomy led to resolution of the hypertrophy. Furthermore, the three children fol- snoring and recurrent otitis media. Cardiac lowed in the outpatient clinic showed stable or catheterisation at 4 years showed worsening room air oxygenation (Figure). The age noticeable failure to improve room air oxygenation over time in improvement in with copyright. his pulmonary hypertension, these patients is in considerable contrast to 22 other room air pulmonary artery pressure of 33 mm Hg. In bronchopulmonary dysplasia patients on home addition, TcPo2 monitoring during sleep showed oxygen treatment who have been followed during resolution of his sleep hypoxaemia. He is doing well and and no longer requires supplemental oxygen at 5 infancy have been reported previously.3 years of age. Discussion Case 4. A boy born at 26 weeks' gestation and weighing 680 g required intubation and positive These four infants had unexpected but serious http://adc.bmj.com/ pressure ventilation on day 2 of life because of cardiopulmonary pathology unrelated to their bron- severe respiratory distress from hyaline membrane chopulmonary dysplasia which contributed to their disease. He developed radiographic and clinical poor clinical status. All had poor growth, static evidence of bronchopulmonary dysplasia. His oxygen requirements, and persistent right ventricu- course was marked by frequent failures at extuba- lar hypertrophy (Table). The coexisting lesions were tion because of upper lobe atelectasis and numerous diverse, and although cardiac catheterisation identi- reintubations. He was finally extubated successfully fied the problems in two, further evaluation, includ- at 103 days and was discharged at 4 months of age, ing bronchoscopy and monitoring of respiratory on September 28, 2021 by guest. Protected requiring half a litre of oxygen per minute by nasal pattern and oxygenation during sleep, were neces- cannula to maintain TcPo2 greater than 7*3 kPa (55 sary to uncover the pathology in the other two mm Hg) during sleep, feeds, and while awake. He children. required frequent admissions to hospital for reactive This is the first report of a group of patients with airways disease and viral pneumonias in spite of his bronchopulmonary dysplasia and severe existing home treatment of isoetharine, theophylline, and cardiopulmonary defects. The three patients fol- frusemide. He also showed poor growth, develop- lowed as outpatients represent five per cent of our mental delay, and cor pulmonale. Because of outpatients with bronchopulmonary dysplasia who clinical and echocardiographic evidence of persis- required home oxygen treatment between 1979 and tent right ventricular hypertrophy and frequent 1981. It is important to note that in each case the hospital admissions he underwent cardiac infant's poor progress was originally attributed to catheterisation at 10 months of age. At this time his the diagnosis of bronchopulmonary dysplasia, thus pulmonary artery pressure was 30 mm Hg when delaying recognition of the other cardiopulmonary breathing room air (Pao2, 5-6 kPa (42 mm Hg)) and abnormalities. Though difficult to detect, each Arch Dis Child: first published as 10.1136/adc.59.10.966 on 1 October 1984. Downloaded from

Unsuspected cardiopulmonary complications of BPD 969 Table Clinical summary offourpatients with bronchopulmonary dysplasia and coexisting cardiopulmonary abnormalities

Case Clinical course Age at diagnosis Findings Treatment Outcome No of coexisting lesion (years) 1 Poor growth 0-8 ASD, PDA, PHT Surgical correction Improvement Persistent RVH Continual high 02 requirement

2 Poor growth 3-0 ASD, VSD, PDA, Surgical correction Death on day 2 Persistent RVH PHT, interrupted after operation Severe hypoxaemia aortic arch 3 Poor growth 2-5 Nocturnal hypoxaemia Tonsillectomy and Improvement Frequent hospital admissions from obstructing adenoidectomy for CHF and respiratory distress tonsils Persistent RVH Nocturnal cough, snoring

4 Poor growth 16 Subglottic cyst Resection Improvement Frequent hospital admissions Tracheostomy for RAD Continual high 02 requirement Persistent RVH RVH=right ventricular hypertrophy; CHF=congestive heart failure; RAD=reactive airways disease; ASD=atrial septal defect; PDA=patent ductus arteriosus; PHT=pulmonary hypertension; VSD=ventricular septal defect.

8 infants with bronchopulmonary dysplasia during infancy (Figure). Growth, oxygenation, and dura- tion of ventilation while in the intensive care unit copyright. if were not different in the infants with coexisting cardiopulmonary lesions when compared with other infants with bronchopulmonary dysplasia. Clinical A Ccase1 o- - differences became apparent only during the follow Case 3 o up period. ICase4lx-----z We have noted poor growth, static oxygen requirement, and persistence of right ventricular as . . hypertrophy important findings that prompted http://adc.bmj.com/ 3 6 9 12 15 18 more extensive and invasive diagnostic evaluations Age ( months) of these patients. The time course of improvement Figure Serial room air TcPo2 measurements in the three in these parameters in patients with uncomplicated patients followed in the outpatient clinic. The solid line bronchopulmonary dysplasia is not described in represents mean TcPo2 values of22 other infants with detail. Previous studies have shown that these bronchopulmonary dysplasia managed on home oxygen infants tend to have poor growth, persistent respira- therapy. (Bars represent mean (SD)). tory distress, and frequent hospital admissions

(often due to respiratory infections) after discharge on September 28, 2021 by guest. Protected Conversion-SI to traditional units: TcPo2 1 kPa-7-5 mm Hg. from the neonatal intensive care unit.4 6 7 8 Clinical improvement, as measured by a reduction in hospi- tal admissions, is often seen in the second year of coexisting abnormality was at least potentially re- life, and frequent hospital admissions thereafter parable. We suggest that earlier diagnosis of these may suggest a need for further evaluations. Unfortu- lesions would probably have resulted in fewer nately, frequency of admissions is a crude estimate admissions to hospital, shortened duration of of clinical status and may be influenced considerably oxygen requirement, improved growth, and perhaps by seasonal shifts in virulence of the respiratory allowed survival of patient 2. viruses prevalent in the community. Since most Failure of infants with bronchopulmonary dyspla- infants with bronchopulmonary dysplasia steadily sia to improve their resting TcPo2 should prompt reduce their need for supplemental oxygen,5 6 evaluation of their cardiovascular and upper airway however, a static oxygen requirement over several status. Patient 4, for example, showed little im- months, as shown by our three infants, may be a provement in room air TcPo2 compared with other more sensitive and useful indicator of clinical status. Arch Dis Child: first published as 10.1136/adc.59.10.966 on 1 October 1984. Downloaded from

970 Abman, Accurso, and Bowman Infants with bronchopulmonary dysplasia tend to though perhaps episodic, hypoxaemia. Specifically, require oxygen for variable but often long durations the oxygen therapy may be inadequate to prevent after hospital discharge, ranging from 9 to 75 weeks intermittent hypoxaemia during activity or sleep. (mean 29*9 weeks) in one study.5 Serial measure- Whatever the cause, oxygen therapy may need ments of TcPo2 while breathing room air may be adjustment. Furthermore, these children may need more useful than the absolute duration of oxygen more extensive evaluation to rule out additional therapy in assessing the need for an additional cardiopulmonary problems. Studies such as bron- cardiopulmonary evaluation. Although rates of im- choscopy, echocardiography, cardiac catheterisa- provement of room air TcPo2 are widely variable, tion, and respiratory monitoring for hypoxaemia infants with bronchopulmonary dysplasia generally and sleep apnoea may be important steps in the show steady improvement,6 which three of our diagnostic evaluation. We suggest that the longer a infants failed to show. serious coexisting cardiopulmonary lesion remains We have also found persistence of right ventricu- undiagnosed and uncorrected the more severe will lar hypertrophy to be a valuable indicator of be the patient's course. potential coexisting abnormalities. Although pre- vious studies2 9 10 have shown a high incidence of This work was supported in part by grants from the Cystic Fibrosis this in infants with bronchopulmonary dysplasia, Foundation, National Institutes of Health (HD 00781), and only the study of Harrod et al followed serial American and Colorado Heart Associations. SHA is a fellow of the electrocardiographic tracings after nursery dis- Cystic Fibrosis Foundation. CMB is a Clinician Scientist Awardee charge." In this study, seven of 12 patients with of the American Heart Association. The authors appreciate the bronchopulmonary dysplasia had electrocardio- assistance of Rose Marie Vukovich in the preparation of this graphic evaluation both in the neonatal care unit manuscript. and during follow up. Six patients initially showed right ventricular hypertrophy. At a mean follow up References of 2-7 years (range 1 to 5 years), five showed Northway WH, Rosen RC, Porter DY. Pulmonary disease

persistent right ventricular hypertrophy and resolu- following respiratory therapy of hyaline membrane disease. N copyright. tion had occurred in only one infant. In contrast, we Engl J Med 1967;276:357-68. 2 Johnson JD, Malachowski NC, Grobstein R, et al. Prognosis of have observed that most patients with bronchopul- children surviving with the aid of mechanical ventilation in the monary hyperplasia do not have right ventricular newborn period. J Pediatr 1974;84:272-6. hypertrophy at 1 year of age, even if they had it 3 Edwards DK, Dyer W, Northway WH. Twelve years experience during the initial hospital admission,6 and hence we with bronchopulmonary dysplasia. Pediatrics 1977;59:839-46. as an 4 Markestad T, Fitzhardinge PM. Growth and development in regard persistent right ventricular hypertrophy children recovering from bronchopulmonary dysplasia. J Pediatr important sign of the need for further investigations. 1981 ;98:597-602.

A likely explanation for this difference between the 5 Campbell AN, Zarfin Y, Groenveld M, Bryan MH. Low flow http://adc.bmj.com/ two studies is that our patients were treated with oxygen therapy in infants. Arch Dis Child 1983;58:795-8. whereas those in 6 Abman SH, Accurso FJ, Koops BL. Experience in the continuous home oxygen therapy outpatient management of infants with bronchopulmonary the study of Harrod et al were not and might, dysplasia on home oxygen. Clin Pediatr 1984; (in press). therefore, have been subject to episodic hypox- 7 Mayes L, Perkett E, Stahlman M. Severe bronchopulmonary aemia. dysplasia: a retrospective review. Acta Paediatr Scand 1983;72: 225-9. The importance of this report is the finding of 8 Yu VYH, Orgia AA, Lim SB, et al. Growth and development of severe, unexpected, but treatable cardiopulmonary very low birthweight infants recovering from bronchopulmonary abnormalities in patients with bronchopulmonary dysplasia. Arch Dis Child 1983;58:791-4. on September 28, 2021 by guest. Protected Although logic suggests that a few chil- 9 Fouron JC, Leguennec JC, Villemont D, et al. Value of dysplasia. echocardiography in assessing outcome of bronchopulmonary dren should have coexisting pathology, such defects dysplasia of the newborn. Pediatrics 1980;65:529-35. may go unrecognised as physicians attribute persis- 10 Halliday HL, Dumpit FM, Brady JP. Effects of inspired oxygen tent signs of respiratory distress, cor pulmonale and on echocardiographic assessment of pulmonary vascular resist- slow improvement in oxygenation to the abnormal ance and myocardial contractility in BPD. Pediatrics 1980;65:536-40. lung mechanics and hypoxia of the lung disorder. In Harrod JR, L'Heureux P, Wangensteen DD, Hunt CE. Long- addition, it may be difficult to interpret subtle term follow-up of severe respiratory distress syndrome treated changes in clinical or radiographic examination in with IPPB. J Pediatr 1974;84:277-86. these patients. We suggest that persistent right Correspondence to Dr S H Abman, 4200 East Ninth Avenue, Box ventricular hypertrophy in bronchopulmonary dys- C 220, Denver, Colorado 80262, USA. plasia, even among those receiving continuous supplemental oxygen, may be a sign of persistent, Received 4 July 1984