D I A G N O S I S
OF
BPD
W i l l i a m H. T o o l e y , M o d e r a t o r
Bronchopulmonary dysplasia." Clinical presentation Eduardo Bancalari, M.D.,* George E. Abdenour, M.D., Rosalyn Feller, R. N., and June Gannon, R.N., Miami, Fla.
THE INTRODUCTION of mechanical ventilation in the management of the newborn with respiratory failure has improved the survival of these patients, but it has also increased the incidence of complications associated with this mode of treatment. One of these complications is bronchopulmonary dysplasia, a residual chronic lung disease first described by Northway, R0san, and Porter in 1967.1 Numerous reports have been published subsequently on the subject, but little progress has been made to determine the exact incidence, the pathogenesis, or the best management of this condition. METHOD In order to define some of the clinical characteristics and the possible relationship between chronic lung damage and the mode of respiratory assistance, we reviewed the records of ten patients admitted to the Newborn Service at the University of Miami/Jackson Memorial Medical Center who developed BPD during the year 1978. The diagnosis of BPD was made in cases that fulfilled the following criteria: (1) Required intermittent positive pressure ventilation during the first week of life and for a minimum of three days. (2) Developed clinical signs of chronic respiratory disease characterized by tachypnea, intercostal and subcostal retraction, and tales on auscultation, all persisting for longer than 28 days. (3) Required supplemental oxygen for more than 28 days to maintain a Pa% over 50 mm Hg. (4) Chest radiograph showed persistent strands of densities in both lungs, alternating with areas of normal or increased lucency. In some infants, these areas became coalescent into larger structures resembling bullae. RESULTS Incidence of BPD. Following the criteria described above, there were ten infants who developed BPD during a ten-month period. In order to determine the incidence
From the Department of Pediatrics, University of Miami~School of Medicine. *Reprint address: Department of Pediatries (R-131), University of Miami~School of Medieine, P.O. Box 016960, Miami, FL 33101.
0022-3476/79/110819 + 05500.50/0 9 1979 The C. V. Mosby Co.
of BPD it is necessary to define the population that is at risk. The incidence of BPD is 4.2% if we take as the base population the 235 infants that were ventilated for different indications during the same ten-mont h period. Taking the 182 infants who required IPPV because of RDS, the incidence becomes 5.5%. Since the indications for IPPV are different from one center to another, and because it is unlikely that infants ventilated for less than three days will develop BPD, one can consider only the 87 infants with RDS who were ventilated for more than three days. In this case the incidence increases to 11.5%. Finally, the mortality rate of infants who require IPPV also influences the incidence of BPD. It is likely that the increased survival of infants with RDS and infants of verY low gestational age increases the number of patients susceptible to develop BPD. Taking only the 69 infants who required IPPV for more than three days and survived more than 30 days, the time that it usually takes for the chronicchanges to become Clinically and radiographically evident, the incidence increases to 14.5%. Abbreviations used BPD: bronchopulmonary dysplasia IPPV: intermittent positive pressure ventilation RDS: respiratory distress syndrome PDA: patent ductus arteriosus Patient's characteristics. Four infants were born at our hospital; the other Six were referred from outside hospitals (Tabl e I). Seven of the ten infants were males, a sex ratio distribution similar to that of infants with severe RDS in our service. All patients were born prematurely, with gestational ages between 27 and 35 weeks and birth weights between 920 and 1,560 gin. Three infants had Apgar scores Of 1 at one minute, but at 5 minutes all but one infant had Apgar scores of 6 or higher. Clinical course. All infants in this series had RDS and all but one needed IPPV during the first 12 hours of life. Six patients showed an initial improvement in their RDS, and only after the first week of life did their course start to deteriorate, leading to the chronic lung changes. Five of the ten infants had a pneumothorax and six had radiographic evidence of pulmonary interstitial emphysema during the first week of life. Nine of the ten patients had a clinical patent ductus \
TheJournalofPEDIATRlCS
819
Workshop on BPD
820
The Journal of Pediatrics November 1979
I
Table
Patient
Place of birth
Sex
Gestational age (wk)
Ma Wi
Outborn Outborn
M F
29 28
980 920
Hu Ri
Inborn Outborn
M F
3l 27
Br Ko
Outborn Outborn
M M
Do Te Au Ne
Outborn Inborn Inborn Inborn
M F M M
Birth weight (gin)
Apgar score
I Diagnosis
Age 1PPV begun (hr)
Pneumothorax
PIE
PDA
+ --
---
+ +
3-7 5-7
RDS RDS
8-8 1-3
RDS RDS
4 144
+ +
+ -
+
1,100
33 31
1,495 1,560
6-9 1-6
RDS
1 Birth
+
RDS
+ +
+ +
35 30 33 32
1,260
-
950 1,310 1,420
1-6
RDS RDS RDS RDS
1.5 Birth Birth 1.5
+ + + -
+ + + +
1,000
4-6 7-9
8.5 " 2
-
+ -
Abbreviations used: tPPV = Intermittent positive pressure ventilation; RDS = respiratory distress syndrome; PIE = pulmona~ interstitial emphysema; PDA = Patent ductus arteriosus. Table
II
Patient
Type ventilator*
0., concentration first week 9 (hr) > 70%' I > 40% > 21%
Peak inspiratory pressure (cm H20) first week (hr)
i
> 40
30-40
< 30
IPP V (days)
Hospitalization (days)
Outcome
i
Ma
Bi
13.2
68.5
144
0
73
94
133
S
Wi Hu
Bo Bo
7.5 55
124.5 113
168 168
0 6
58 1(i2
105 0
9.5 84
173 155
S D
Ri
Bi
23.5
61.5
158
0
55
45
6.4
398
S
Br
Bo
164
168
0
163
1
Ko Do Te
Bo Bi Bi
117 102 52.9
160.5 168 168
0 0 0
87 98 49
56 67 119
168
168
44
38
86
168
0
Au
Bo
Ne
Bo
116 39.5 13 6.2 153 0.5
0.3
94
' 20
43 8.6 10 6.2 137 6.3
55
D
68 135 164
S S S
169
D
118
S
Abbreviations used: IPPV = Intermittent positive pressure ventilation; S = survived; D = died. *Bi = Baby Bird; Bo = Bourns BP 200. arteriosus associated with failure of the left heart that was managed medically by fluid restriction, diuretics, and digitalis. Respiratory assistance. All ten infants required IPPV because of respiratory failure secondary to R D S (Table II). They were ventilated With a Baby Bird or h Botlrns BP 200 used as time and pressure limited devices, with inspirat0ry times b e t w e e n 0.5 and 0.8 of a second. Six patients had only moderate disease, requiring less than 24 hours of oxygen concentration~ ~bove 70% during the first week. Only two infant s requfi:ed more than 70% 02 for more than three days. All patients requ!red peak airway pressure above 30 cm H20 during the first week of life, but only two received pressures over 40 cm H:O.
The duration of IPPV ranged from six to 137 days. After being weaned from t h e velatilator, all i n f a n t s required supplemental oxygen for long periods of time and had persistently e l e v a t e d Pae%. Seven infants survived and were discharged h o m e in good condition not requiring additional ox~(gen or other treatment; all of these infaflts had some residual radiographic changes and mild respiratory symptoms. Three infants died during their hospital course be!ween the ages o f 8 and 24 weeks of life. Two of them died because of severe respiratory failure that could not be controlled with mechanical ventilation and increased inspired oxygen concentrations. The third died due to severe neurologic damage secondary to intracranial hemori'hage. However, at the time of
Volume 95 Number 5, part 2
his death, his pulmonary function was markedly improved. In five of the ten infants, pulmonary artery pressure was assessed indirectly by echocardiography. At the time of the measurement all infants were in Stable condition, but still requiring supplemental oxygen to maintain a Pa% over 50 mm Hg. The ratio between the right ventricular pre-ejection period over the ejection time was within normal limits ( < 0.30) in all infants, suggesting that their pulmonary artery pressure was not increased. DISCUSSION Many of the discrepancies found in the literature regarding incidence, pathogenesis, and outcome of BPD are in part due to a lack of a standard definition of BPD. It is often difficult or impossible to differentiate clinically Stages I, II, and Ill of BPD as originally described by Northway, from the normal course of severe RDS. Radiographically, Stages I a n d II are also indistinguishable from severe RDS. On the other hand, half of our patients developed BPD Stage IV without passing through the early clinical or radiographic stages. For these reasons, we have decided to restrict the diagnosis of BPD only to the more advanced stages of the disease. By doing this, we are excluding cases of BPD in early stages, but at the same time, we are eliminating infants who have severe RDS or RDS complicated with a patent ductus arteri0sus, pulmonary hemorrhage, or a superimposed infection, Who would be diagnosed as having B P D i f a more loose definition is used. The same difficulty occurs when the diagnosis of BPD is made in infants who die during the first weeks o f life, based on the histologic changes described by Northway et al in Stages I and II of the disease. These changes are likely to be present in most infants with RDS who are ventilated with high oxygen concentrations for more than three days. 2 Although these changes may represent early stages of BPD, in most cases they will not progress and will resolve after the infant is weaned from the ventilator. These difficulties in defining BPD, plus differences in the base population, may help to explain partially the discrepancies in the reported incidence of BPD, which Varies between 5 and 46%. 3-~ Most infants who develo p BPD, as in the present series, are premature infants, but BPD has also been described in infants born at term. 1 3 The fact that most infants with BPD are born prematurely may indicate a higher susceptibility of this group. However, it may also reflect the higher incidence of RDS and need for IPPV in small infants. No relationship has been found between BPD and maternal problems or BPD and labor and delivery complications. ~
Diagnosis of BPD
821
Because the majority of infants developing BPD have RDS and require mechanical ventilation, both RDS and IPPV h a v e been considered important factors in the pathogenesis of BPD. All infants in the present series had RDS and all but one needed IPPV during the first 12 hours of life. Nevertheless, six infants showed initial improvement in their RDS and only after the first week of life did their course start to deteriorate, leading to the chronic lung changes. There are reported instances of infants developing BPD after IPPV was used for apnea of prematurity or after surgery for a PDA. 7' 8 In this situation, it is difficult to rule out the possibility that the pulmonary changes correspond to the Wilson-Mikity syndrome 9 unless there is pathologic confirmation of BPD. The same applies to one case of BPD reported by Edwards et aP in an infant treated only with continuous positive airway pressure. It is conceivable that infants who require IPPV because of Wilson-Mikity syndrome, chronic pulmonary insufficiency of prematurity, 1~or other cardiopulmonary problems such as a PDA or pneumonia may develop chronic lung changes similar to those seen in infants ventilated because of RDS. The end-stage will be indistinguishable and only the clinical course prior to the chronic respiratory disease will permit a different classification of these infants. Whether this separation is of practical importance or not is questionable. Nearly all reported cases of BPD have occurred in infants who required intermittent positive pressure ventilation. Because the indication for IPPV. in most instances. is respiratory failure due to RDS. it is difficult to separate the role of the RDS from that of IPPV in the genesis of the chronic pulmonary damage. The more severe the respiratory failure, the more aggressive becomes the ventilatory support and the higher the chance for pulmonary damage. It has been emphasized in the literature that infants surviving ventilation with intermittent negative pressure do not develop this problem in spite of receiving high concentrations of oxygen for extended periods of time? ~ implying that the positive pressure plays a predominant role in BPD. In our experience, all infants developing BPD were ventilated with IPPV because of RDS. but some of the cases were mild, reqmrmg relatively low airway pressures and oxygen concentrations. Only two infants required more than 70% O2 for more than three days. This relatively low oxygen requirement has also been described by others, 7 suggesting that oxygen, although it may play a role, is not a critical factor in the development of BPD. The total time of exposure to O2 in infants with BPD is always prolonged, but rather than the cause, this becomes the necessary treatment for their pulmonary failure. The other factor thought to be related to the develop-
822
Workshop on B P D
ment of BPD is the peak airway pressure generated during the IPPV? ~ This theory, although very provocative from the pathophysiologic and morphologic points of view, has not been confirmed in other studies? 3 Only two of our ten patients with BPD required more than 40 cm H~O peak airway pressure during IPPV. As mentioned earlier, the duration and intensity of mechanical ventilation, like the duration of oxygen therapy, are usually consequences of the disease and therefore the importance of their roles as possible causes of BPD is difficult to elucidate retrospectively. Preliminary results from a prospective study currently in progress in our service do not support the theory that high peak airway pressures used early during the course of RDS are important in the pathogenesis of BPD. Alveolar overdistension and rupture secondary to the positive pressure may also play a role in BPD. In our ten patients, five had pneumothorax and six had radiographic evidence of pulmonary interstitial emphysema. This incidence is higher than in our general population of infants requiring IPPV, confirming similar data from the literature: TM Nine of the ten infants had a clinical patent ductus arteriosus that required medical management. This high incidence of PDA in infants with BPD has also been a consistent finding in most reported series. 1 ~2 Excessive fluid intake can aggravate the left heart failure in patients with PDA and possibly increase the risk of developing BPD, as recently suggested by Brown et al. 15 A complication mentioned frequently in infants with BPD is right heart failure secondary to pulmonary hypertension. We did not find echocardiographic signs of pulmonary hypertension in the five infants with chronic lung disease studied. This unexpected finding may be the result of our special effort to keep the Pao 2 over 50 mm Hg at all times in these patients, eliminating hypoxemia as one of the causes of pulmonary hypertension. TM The mortality of infants with BPD varies in different reports. In Edwards' series, ~ 24 of 62 infants with BPD Stage IV died. Death is usually due to progressive respiratory failure, cor pulmonale, or recurrent infections. Three of our ten patients died. Survivors usually remain in respiratory failure for long periods of time and require special care for periods of months or years. Their course is frequently complicated by recurrent infections, heart failure due to PDA, or cor pulmonale. The heart failure requires fluid restriction and this, plus difficulty in supplying enough oral intake, makes adequate nutrition very difficult. Chronic hospitalization and additional oxygen requirement cause isolation of these infants from a normal environment, depriving them of the normal parental
The Journal of Pediatrics November 1979
influence during a critical stage of development. This, plus repeated painful stimulation produced by blood sampling, suction, physiotherapy, nasogastric feeding, etc., may have a profound negative influence in the psychosocial development of these infants. This important aspect has not yet been adequately investigated. The pulmonary function usually improves gradually over a period of several months and the oxygen requirement decreases while the Pac% approaches normal values. Most of the survivors can be discharged from the hospital between 3 and 6 months of age; but in some cases the hospital stay is much longer. No detailed information is available on the long-term outcome of survivors except that they require frequent readmissions to the hospital because of aggravation of their respiratory symptoms during acute respiratory infections, usually with evidence of small airway obstruction.l~. 17. 18 It is not clear whether pulmonary function will revert to normal after several years or whether these infants will be more susceptible to respiratory problems later in life. REFERENCES
1. Northway WH, Rosan RC, and Porter DY: Pulmonary disease following respirator therapy of hyaline-membrane disease, N Engl J Med 276:357, 1967. 2. Banerjee CK, Girling D J, and Wigglesworth JS: Pulmonary fibroplasia in newborn babies treated with oxygen and artificial ventilation, Arch Dis Child 47:509, 1972. 3. Rhodes PG, Hall RT, and Le0nides JC: Chronic pulmonary disease in neonates With assisted ventilation, Pediatrics 55:788, 1975. 4. Berg TJ, Pagtakhan RD, Reed MH, et al: Bronchopulmonary dysplasia and lung rupture in hyaline membrane disease: Influence of continuous distending pressure, Pediatrics 55:51, 1975. 5. Ehrenkranz RA, Bonta BW, Ablow RC, et al: Amelioration of bronchopulmonary dysplasia after vitamin E administration, N Engl J M ed 299:564, 1978. 6. Edwards DK, I~eL"WM, and Northway WH: Twelve year's experience with bronchopulmonary dysplasia, pediatrics 59:839, 1977. 7. Philip AGS: Oxygen plus pressure plus time: The etiology of bronchopulmonary dysplasia, Pediatrics 55:44, 1975. 8. Firis-Hansen B, Kamper J, Boison-Moller J, et al: The incidence of pulmonary fibroplasia among 263 infants treated with intermittent positive pressure ventilation, in Stetson JB, and S~vyerPR, editors: Neonatal intensive care, St.. Louis, 1976, Warren H Green, Inc., p 445. 9. Wilson MG, and Mikity VG: New form of respiratory disease in premature infants, J Dis Child 99:489, 1960. 10. Krauss AN, Klain, DB, and Auld PAM: Chronic pulmonary insufficiency of prematurity (CPIP), Pediatrics 55:55, 1975. 11. Stern L, Ramos A, Outerbridge EW, et al: Negative pressure artificial respiration use in treatment of respiratory failure of the newborn, Can Med Assoc J 102:595, 1970.
Volume 95 Number 5, part 2 12. Taghizadeh A, and Reynolds EOR: Pathogenesis of bronchopulmonary dysplasia following hyaline membrane disease, Am J Pathol 83:241, 1976. 13. Boros SJ, and Orgill AA: Mortality and morbidity associated with pressure- and volume-limited infant ventilators, Am J Dis Child 132:856, 1978. 14. WattsJL, Ariagno RL, Brady JP, et al: Chronic pulmonary disease in neonates after artificial ventilation: Distribution of ventilation and pulmonary interstitial emphysema, Pediatrics 60:273, 1977. 15. BrownER, Stark A, Sosenko I, Lawson EE, and Avery ME: Bronchopulmonary dysplasia: Possible relationship to pulmonary edema, J PEDIATR92:982, 1978.
Diagnosis" o f BPD
823
16. MelnickG, Pickoff A, Ferrer PL, et al: Echocardiographic assessment of the pulmonary vascular resistance in young infants with bronchopulmonary dysplasia, Clin Res 26:808A, 1978. 17. Johnson JD, Malachowski NC, Grobstein R, et al: Prognosis of children surviving with the aid of mechanical ventilation in the newborn period, J PEDIATR84"272, 1974. 18. Harrod JR, L'Heureux P, Wahgensteen OD, et al: Longterm follow-up of severe respiratory distress syndrome treated with IPPB, J PED~ATR84"277, 1974.
Radiographic aspects of bronchopulmonary dysplasia David K. Edwards, M.D., San Diego, Calif.
I N 1 9 6 7, Northway and associates I described a form of chronic lung disease that they named bronchopulmonary dyplasia, basing their observations on newborn infants who received assisted ventilation for respiratory distress syndrome between 1962 and 1966. This disease appeared to progress through a series of four stages that were radiographically and pathologically distinct, terminating in chronic lung disease (Stage IV BPD). The radiographic appearance at each stage was characteristic, with Stage I appearing identical to uncomplicated RDS, Stage II being a period of pulmonary parenchymal opacity that cleared into a bubbly appearance (Stage III), which often ultimately became the rather distinctive pattern of chronic BPD (Stage IV).'-'Stage IV was defined chronologically as bubbly-appearing lungs persisting for 30 days or more. Subsequently this disease was observed by numerous investigators and described under a variety of names, including bronchopulmonary dysplasia, 3-1-~ pulmonary fibroplasia, 1~-1~ chronic pulmonary disease, TM respirator lung disease, ,~ and other descriptive terms? 9 -~ In most reports the diagnosis of BPD implies chronic disease, or Stage IV BPD. For most purposes, except when evolution of the condition is being discussed, this would appear to be a satisfactory convention. Since the initial descriptions of BPD, the disease appears to have changed, at least in certain of its radiographic manifestations. This article is a discussion of several recent observations, with particular emphasis on radiographic features and manifestations.
From the Departments of Radiology and Pediatrics, University of California, San Diego. Reprint address: Department of Radiology, University Hospital 225 Dickinson St., San Diego. CA 92103.
0022-3476/79/110823 + 07500.70/0 9 1979 The C. V. Mosby Co.
RECENT OBSERVATIONS Pathogenesis. In the initial series of Northway et al, 1 all patients who developed BPD required ventilatory assistance for underlying RDS; these authors speculated that the presence of RDS might have contributed to the lesions observed. Subsequently, the appearance of BPD has been noted in patients with a wide variety of initial conditions, including esophageal atresia and aspiration pneumonia, 1~ neonatal tetanus, TM congenital heart disease, ~7a congenital muscular disorder, ~8 and meconium aspiration @ndrome? ~ The author has observed several examples of Abbreviations used BPD: bronchopulmonary dysplasia RDS: respiratory distress syndrome radiographic BPD in patients with "immature lung syndrome, ''-~9 who required oxygenation and ventilatory assistance for apnea neonatorum and/or patent ductus arteriosus, and in two patients similarly treated for tetralogy of Fallot. It would appear from such patients that the presence of RDS is not a necessary condition for the subsequent development of BPD. The similarity of radiographic changes ultimately seen in this wide variety of diseases strongly suggests that factors of treatment, rather than long-term effects of the underlying disease, are of etiologic importance. Other conditions that may be identified radiographically have also been associated with the development of BPD. For example, some investigators have noted an association with ligation of a patent ductus arteriosus, ~~ although this experience is not universal.~ Another report has described a relationship with fluid overload?' Pulmonary interstitial emphysema has been associated with the development of BPD, :~3 and of a series of 12 newborn
OF
BPD
W i l l i a m H. T o o l e y , M o d e r a t o r
Bronchopulmonary dysplasia." Clinical presentation Eduardo Bancalari, M.D.,* George E. Abdenour, M.D., Rosalyn Feller, R. N., and June Gannon, R.N., Miami, Fla.
THE INTRODUCTION of mechanical ventilation in the management of the newborn with respiratory failure has improved the survival of these patients, but it has also increased the incidence of complications associated with this mode of treatment. One of these complications is bronchopulmonary dysplasia, a residual chronic lung disease first described by Northway, R0san, and Porter in 1967.1 Numerous reports have been published subsequently on the subject, but little progress has been made to determine the exact incidence, the pathogenesis, or the best management of this condition. METHOD In order to define some of the clinical characteristics and the possible relationship between chronic lung damage and the mode of respiratory assistance, we reviewed the records of ten patients admitted to the Newborn Service at the University of Miami/Jackson Memorial Medical Center who developed BPD during the year 1978. The diagnosis of BPD was made in cases that fulfilled the following criteria: (1) Required intermittent positive pressure ventilation during the first week of life and for a minimum of three days. (2) Developed clinical signs of chronic respiratory disease characterized by tachypnea, intercostal and subcostal retraction, and tales on auscultation, all persisting for longer than 28 days. (3) Required supplemental oxygen for more than 28 days to maintain a Pa% over 50 mm Hg. (4) Chest radiograph showed persistent strands of densities in both lungs, alternating with areas of normal or increased lucency. In some infants, these areas became coalescent into larger structures resembling bullae. RESULTS Incidence of BPD. Following the criteria described above, there were ten infants who developed BPD during a ten-month period. In order to determine the incidence
From the Department of Pediatrics, University of Miami~School of Medicine. *Reprint address: Department of Pediatries (R-131), University of Miami~School of Medieine, P.O. Box 016960, Miami, FL 33101.
0022-3476/79/110819 + 05500.50/0 9 1979 The C. V. Mosby Co.
of BPD it is necessary to define the population that is at risk. The incidence of BPD is 4.2% if we take as the base population the 235 infants that were ventilated for different indications during the same ten-mont h period. Taking the 182 infants who required IPPV because of RDS, the incidence becomes 5.5%. Since the indications for IPPV are different from one center to another, and because it is unlikely that infants ventilated for less than three days will develop BPD, one can consider only the 87 infants with RDS who were ventilated for more than three days. In this case the incidence increases to 11.5%. Finally, the mortality rate of infants who require IPPV also influences the incidence of BPD. It is likely that the increased survival of infants with RDS and infants of verY low gestational age increases the number of patients susceptible to develop BPD. Taking only the 69 infants who required IPPV for more than three days and survived more than 30 days, the time that it usually takes for the chronicchanges to become Clinically and radiographically evident, the incidence increases to 14.5%. Abbreviations used BPD: bronchopulmonary dysplasia IPPV: intermittent positive pressure ventilation RDS: respiratory distress syndrome PDA: patent ductus arteriosus Patient's characteristics. Four infants were born at our hospital; the other Six were referred from outside hospitals (Tabl e I). Seven of the ten infants were males, a sex ratio distribution similar to that of infants with severe RDS in our service. All patients were born prematurely, with gestational ages between 27 and 35 weeks and birth weights between 920 and 1,560 gin. Three infants had Apgar scores Of 1 at one minute, but at 5 minutes all but one infant had Apgar scores of 6 or higher. Clinical course. All infants in this series had RDS and all but one needed IPPV during the first 12 hours of life. Six patients showed an initial improvement in their RDS, and only after the first week of life did their course start to deteriorate, leading to the chronic lung changes. Five of the ten infants had a pneumothorax and six had radiographic evidence of pulmonary interstitial emphysema during the first week of life. Nine of the ten patients had a clinical patent ductus \
TheJournalofPEDIATRlCS
819
Workshop on BPD
820
The Journal of Pediatrics November 1979
I
Table
Patient
Place of birth
Sex
Gestational age (wk)
Ma Wi
Outborn Outborn
M F
29 28
980 920
Hu Ri
Inborn Outborn
M F
3l 27
Br Ko
Outborn Outborn
M M
Do Te Au Ne
Outborn Inborn Inborn Inborn
M F M M
Birth weight (gin)
Apgar score
I Diagnosis
Age 1PPV begun (hr)
Pneumothorax
PIE
PDA
+ --
---
+ +
3-7 5-7
RDS RDS
8-8 1-3
RDS RDS
4 144
+ +
+ -
+
1,100
33 31
1,495 1,560
6-9 1-6
RDS
1 Birth
+
RDS
+ +
+ +
35 30 33 32
1,260
-
950 1,310 1,420
1-6
RDS RDS RDS RDS
1.5 Birth Birth 1.5
+ + + -
+ + + +
1,000
4-6 7-9
8.5 " 2
-
+ -
Abbreviations used: tPPV = Intermittent positive pressure ventilation; RDS = respiratory distress syndrome; PIE = pulmona~ interstitial emphysema; PDA = Patent ductus arteriosus. Table
II
Patient
Type ventilator*
0., concentration first week 9 (hr) > 70%' I > 40% > 21%
Peak inspiratory pressure (cm H20) first week (hr)
i
> 40
30-40
< 30
IPP V (days)
Hospitalization (days)
Outcome
i
Ma
Bi
13.2
68.5
144
0
73
94
133
S
Wi Hu
Bo Bo
7.5 55
124.5 113
168 168
0 6
58 1(i2
105 0
9.5 84
173 155
S D
Ri
Bi
23.5
61.5
158
0
55
45
6.4
398
S
Br
Bo
164
168
0
163
1
Ko Do Te
Bo Bi Bi
117 102 52.9
160.5 168 168
0 0 0
87 98 49
56 67 119
168
168
44
38
86
168
0
Au
Bo
Ne
Bo
116 39.5 13 6.2 153 0.5
0.3
94
' 20
43 8.6 10 6.2 137 6.3
55
D
68 135 164
S S S
169
D
118
S
Abbreviations used: IPPV = Intermittent positive pressure ventilation; S = survived; D = died. *Bi = Baby Bird; Bo = Bourns BP 200. arteriosus associated with failure of the left heart that was managed medically by fluid restriction, diuretics, and digitalis. Respiratory assistance. All ten infants required IPPV because of respiratory failure secondary to R D S (Table II). They were ventilated With a Baby Bird or h Botlrns BP 200 used as time and pressure limited devices, with inspirat0ry times b e t w e e n 0.5 and 0.8 of a second. Six patients had only moderate disease, requiring less than 24 hours of oxygen concentration~ ~bove 70% during the first week. Only two infant s requfi:ed more than 70% 02 for more than three days. All patients requ!red peak airway pressure above 30 cm H20 during the first week of life, but only two received pressures over 40 cm H:O.
The duration of IPPV ranged from six to 137 days. After being weaned from t h e velatilator, all i n f a n t s required supplemental oxygen for long periods of time and had persistently e l e v a t e d Pae%. Seven infants survived and were discharged h o m e in good condition not requiring additional ox~(gen or other treatment; all of these infaflts had some residual radiographic changes and mild respiratory symptoms. Three infants died during their hospital course be!ween the ages o f 8 and 24 weeks of life. Two of them died because of severe respiratory failure that could not be controlled with mechanical ventilation and increased inspired oxygen concentrations. The third died due to severe neurologic damage secondary to intracranial hemori'hage. However, at the time of
Volume 95 Number 5, part 2
his death, his pulmonary function was markedly improved. In five of the ten infants, pulmonary artery pressure was assessed indirectly by echocardiography. At the time of the measurement all infants were in Stable condition, but still requiring supplemental oxygen to maintain a Pa% over 50 mm Hg. The ratio between the right ventricular pre-ejection period over the ejection time was within normal limits ( < 0.30) in all infants, suggesting that their pulmonary artery pressure was not increased. DISCUSSION Many of the discrepancies found in the literature regarding incidence, pathogenesis, and outcome of BPD are in part due to a lack of a standard definition of BPD. It is often difficult or impossible to differentiate clinically Stages I, II, and Ill of BPD as originally described by Northway, from the normal course of severe RDS. Radiographically, Stages I a n d II are also indistinguishable from severe RDS. On the other hand, half of our patients developed BPD Stage IV without passing through the early clinical or radiographic stages. For these reasons, we have decided to restrict the diagnosis of BPD only to the more advanced stages of the disease. By doing this, we are excluding cases of BPD in early stages, but at the same time, we are eliminating infants who have severe RDS or RDS complicated with a patent ductus arteri0sus, pulmonary hemorrhage, or a superimposed infection, Who would be diagnosed as having B P D i f a more loose definition is used. The same difficulty occurs when the diagnosis of BPD is made in infants who die during the first weeks o f life, based on the histologic changes described by Northway et al in Stages I and II of the disease. These changes are likely to be present in most infants with RDS who are ventilated with high oxygen concentrations for more than three days. 2 Although these changes may represent early stages of BPD, in most cases they will not progress and will resolve after the infant is weaned from the ventilator. These difficulties in defining BPD, plus differences in the base population, may help to explain partially the discrepancies in the reported incidence of BPD, which Varies between 5 and 46%. 3-~ Most infants who develo p BPD, as in the present series, are premature infants, but BPD has also been described in infants born at term. 1 3 The fact that most infants with BPD are born prematurely may indicate a higher susceptibility of this group. However, it may also reflect the higher incidence of RDS and need for IPPV in small infants. No relationship has been found between BPD and maternal problems or BPD and labor and delivery complications. ~
Diagnosis of BPD
821
Because the majority of infants developing BPD have RDS and require mechanical ventilation, both RDS and IPPV h a v e been considered important factors in the pathogenesis of BPD. All infants in the present series had RDS and all but one needed IPPV during the first 12 hours of life. Nevertheless, six infants showed initial improvement in their RDS and only after the first week of life did their course start to deteriorate, leading to the chronic lung changes. There are reported instances of infants developing BPD after IPPV was used for apnea of prematurity or after surgery for a PDA. 7' 8 In this situation, it is difficult to rule out the possibility that the pulmonary changes correspond to the Wilson-Mikity syndrome 9 unless there is pathologic confirmation of BPD. The same applies to one case of BPD reported by Edwards et aP in an infant treated only with continuous positive airway pressure. It is conceivable that infants who require IPPV because of Wilson-Mikity syndrome, chronic pulmonary insufficiency of prematurity, 1~or other cardiopulmonary problems such as a PDA or pneumonia may develop chronic lung changes similar to those seen in infants ventilated because of RDS. The end-stage will be indistinguishable and only the clinical course prior to the chronic respiratory disease will permit a different classification of these infants. Whether this separation is of practical importance or not is questionable. Nearly all reported cases of BPD have occurred in infants who required intermittent positive pressure ventilation. Because the indication for IPPV. in most instances. is respiratory failure due to RDS. it is difficult to separate the role of the RDS from that of IPPV in the genesis of the chronic pulmonary damage. The more severe the respiratory failure, the more aggressive becomes the ventilatory support and the higher the chance for pulmonary damage. It has been emphasized in the literature that infants surviving ventilation with intermittent negative pressure do not develop this problem in spite of receiving high concentrations of oxygen for extended periods of time? ~ implying that the positive pressure plays a predominant role in BPD. In our experience, all infants developing BPD were ventilated with IPPV because of RDS. but some of the cases were mild, reqmrmg relatively low airway pressures and oxygen concentrations. Only two infants required more than 70% O2 for more than three days. This relatively low oxygen requirement has also been described by others, 7 suggesting that oxygen, although it may play a role, is not a critical factor in the development of BPD. The total time of exposure to O2 in infants with BPD is always prolonged, but rather than the cause, this becomes the necessary treatment for their pulmonary failure. The other factor thought to be related to the develop-
822
Workshop on B P D
ment of BPD is the peak airway pressure generated during the IPPV? ~ This theory, although very provocative from the pathophysiologic and morphologic points of view, has not been confirmed in other studies? 3 Only two of our ten patients with BPD required more than 40 cm H~O peak airway pressure during IPPV. As mentioned earlier, the duration and intensity of mechanical ventilation, like the duration of oxygen therapy, are usually consequences of the disease and therefore the importance of their roles as possible causes of BPD is difficult to elucidate retrospectively. Preliminary results from a prospective study currently in progress in our service do not support the theory that high peak airway pressures used early during the course of RDS are important in the pathogenesis of BPD. Alveolar overdistension and rupture secondary to the positive pressure may also play a role in BPD. In our ten patients, five had pneumothorax and six had radiographic evidence of pulmonary interstitial emphysema. This incidence is higher than in our general population of infants requiring IPPV, confirming similar data from the literature: TM Nine of the ten infants had a clinical patent ductus arteriosus that required medical management. This high incidence of PDA in infants with BPD has also been a consistent finding in most reported series. 1 ~2 Excessive fluid intake can aggravate the left heart failure in patients with PDA and possibly increase the risk of developing BPD, as recently suggested by Brown et al. 15 A complication mentioned frequently in infants with BPD is right heart failure secondary to pulmonary hypertension. We did not find echocardiographic signs of pulmonary hypertension in the five infants with chronic lung disease studied. This unexpected finding may be the result of our special effort to keep the Pao 2 over 50 mm Hg at all times in these patients, eliminating hypoxemia as one of the causes of pulmonary hypertension. TM The mortality of infants with BPD varies in different reports. In Edwards' series, ~ 24 of 62 infants with BPD Stage IV died. Death is usually due to progressive respiratory failure, cor pulmonale, or recurrent infections. Three of our ten patients died. Survivors usually remain in respiratory failure for long periods of time and require special care for periods of months or years. Their course is frequently complicated by recurrent infections, heart failure due to PDA, or cor pulmonale. The heart failure requires fluid restriction and this, plus difficulty in supplying enough oral intake, makes adequate nutrition very difficult. Chronic hospitalization and additional oxygen requirement cause isolation of these infants from a normal environment, depriving them of the normal parental
The Journal of Pediatrics November 1979
influence during a critical stage of development. This, plus repeated painful stimulation produced by blood sampling, suction, physiotherapy, nasogastric feeding, etc., may have a profound negative influence in the psychosocial development of these infants. This important aspect has not yet been adequately investigated. The pulmonary function usually improves gradually over a period of several months and the oxygen requirement decreases while the Pac% approaches normal values. Most of the survivors can be discharged from the hospital between 3 and 6 months of age; but in some cases the hospital stay is much longer. No detailed information is available on the long-term outcome of survivors except that they require frequent readmissions to the hospital because of aggravation of their respiratory symptoms during acute respiratory infections, usually with evidence of small airway obstruction.l~. 17. 18 It is not clear whether pulmonary function will revert to normal after several years or whether these infants will be more susceptible to respiratory problems later in life. REFERENCES
1. Northway WH, Rosan RC, and Porter DY: Pulmonary disease following respirator therapy of hyaline-membrane disease, N Engl J Med 276:357, 1967. 2. Banerjee CK, Girling D J, and Wigglesworth JS: Pulmonary fibroplasia in newborn babies treated with oxygen and artificial ventilation, Arch Dis Child 47:509, 1972. 3. Rhodes PG, Hall RT, and Le0nides JC: Chronic pulmonary disease in neonates With assisted ventilation, Pediatrics 55:788, 1975. 4. Berg TJ, Pagtakhan RD, Reed MH, et al: Bronchopulmonary dysplasia and lung rupture in hyaline membrane disease: Influence of continuous distending pressure, Pediatrics 55:51, 1975. 5. Ehrenkranz RA, Bonta BW, Ablow RC, et al: Amelioration of bronchopulmonary dysplasia after vitamin E administration, N Engl J M ed 299:564, 1978. 6. Edwards DK, I~eL"WM, and Northway WH: Twelve year's experience with bronchopulmonary dysplasia, pediatrics 59:839, 1977. 7. Philip AGS: Oxygen plus pressure plus time: The etiology of bronchopulmonary dysplasia, Pediatrics 55:44, 1975. 8. Firis-Hansen B, Kamper J, Boison-Moller J, et al: The incidence of pulmonary fibroplasia among 263 infants treated with intermittent positive pressure ventilation, in Stetson JB, and S~vyerPR, editors: Neonatal intensive care, St.. Louis, 1976, Warren H Green, Inc., p 445. 9. Wilson MG, and Mikity VG: New form of respiratory disease in premature infants, J Dis Child 99:489, 1960. 10. Krauss AN, Klain, DB, and Auld PAM: Chronic pulmonary insufficiency of prematurity (CPIP), Pediatrics 55:55, 1975. 11. Stern L, Ramos A, Outerbridge EW, et al: Negative pressure artificial respiration use in treatment of respiratory failure of the newborn, Can Med Assoc J 102:595, 1970.
Volume 95 Number 5, part 2 12. Taghizadeh A, and Reynolds EOR: Pathogenesis of bronchopulmonary dysplasia following hyaline membrane disease, Am J Pathol 83:241, 1976. 13. Boros SJ, and Orgill AA: Mortality and morbidity associated with pressure- and volume-limited infant ventilators, Am J Dis Child 132:856, 1978. 14. WattsJL, Ariagno RL, Brady JP, et al: Chronic pulmonary disease in neonates after artificial ventilation: Distribution of ventilation and pulmonary interstitial emphysema, Pediatrics 60:273, 1977. 15. BrownER, Stark A, Sosenko I, Lawson EE, and Avery ME: Bronchopulmonary dysplasia: Possible relationship to pulmonary edema, J PEDIATR92:982, 1978.
Diagnosis" o f BPD
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16. MelnickG, Pickoff A, Ferrer PL, et al: Echocardiographic assessment of the pulmonary vascular resistance in young infants with bronchopulmonary dysplasia, Clin Res 26:808A, 1978. 17. Johnson JD, Malachowski NC, Grobstein R, et al: Prognosis of children surviving with the aid of mechanical ventilation in the newborn period, J PEDIATR84"272, 1974. 18. Harrod JR, L'Heureux P, Wahgensteen OD, et al: Longterm follow-up of severe respiratory distress syndrome treated with IPPB, J PED~ATR84"277, 1974.
Radiographic aspects of bronchopulmonary dysplasia David K. Edwards, M.D., San Diego, Calif.
I N 1 9 6 7, Northway and associates I described a form of chronic lung disease that they named bronchopulmonary dyplasia, basing their observations on newborn infants who received assisted ventilation for respiratory distress syndrome between 1962 and 1966. This disease appeared to progress through a series of four stages that were radiographically and pathologically distinct, terminating in chronic lung disease (Stage IV BPD). The radiographic appearance at each stage was characteristic, with Stage I appearing identical to uncomplicated RDS, Stage II being a period of pulmonary parenchymal opacity that cleared into a bubbly appearance (Stage III), which often ultimately became the rather distinctive pattern of chronic BPD (Stage IV).'-'Stage IV was defined chronologically as bubbly-appearing lungs persisting for 30 days or more. Subsequently this disease was observed by numerous investigators and described under a variety of names, including bronchopulmonary dysplasia, 3-1-~ pulmonary fibroplasia, 1~-1~ chronic pulmonary disease, TM respirator lung disease, ,~ and other descriptive terms? 9 -~ In most reports the diagnosis of BPD implies chronic disease, or Stage IV BPD. For most purposes, except when evolution of the condition is being discussed, this would appear to be a satisfactory convention. Since the initial descriptions of BPD, the disease appears to have changed, at least in certain of its radiographic manifestations. This article is a discussion of several recent observations, with particular emphasis on radiographic features and manifestations.
From the Departments of Radiology and Pediatrics, University of California, San Diego. Reprint address: Department of Radiology, University Hospital 225 Dickinson St., San Diego. CA 92103.
0022-3476/79/110823 + 07500.70/0 9 1979 The C. V. Mosby Co.
RECENT OBSERVATIONS Pathogenesis. In the initial series of Northway et al, 1 all patients who developed BPD required ventilatory assistance for underlying RDS; these authors speculated that the presence of RDS might have contributed to the lesions observed. Subsequently, the appearance of BPD has been noted in patients with a wide variety of initial conditions, including esophageal atresia and aspiration pneumonia, 1~ neonatal tetanus, TM congenital heart disease, ~7a congenital muscular disorder, ~8 and meconium aspiration @ndrome? ~ The author has observed several examples of Abbreviations used BPD: bronchopulmonary dysplasia RDS: respiratory distress syndrome radiographic BPD in patients with "immature lung syndrome, ''-~9 who required oxygenation and ventilatory assistance for apnea neonatorum and/or patent ductus arteriosus, and in two patients similarly treated for tetralogy of Fallot. It would appear from such patients that the presence of RDS is not a necessary condition for the subsequent development of BPD. The similarity of radiographic changes ultimately seen in this wide variety of diseases strongly suggests that factors of treatment, rather than long-term effects of the underlying disease, are of etiologic importance. Other conditions that may be identified radiographically have also been associated with the development of BPD. For example, some investigators have noted an association with ligation of a patent ductus arteriosus, ~~ although this experience is not universal.~ Another report has described a relationship with fluid overload?' Pulmonary interstitial emphysema has been associated with the development of BPD, :~3 and of a series of 12 newborn
