March 1978
The Journal o f P E D 1 A T R I C S
467
Medical management of small preterm infants with symptomatic patient ductus arteriosus During 1975, 38 of 44 infants with a birth weight of 0
< o
nIn
LLI n,'-
15 N =38
-1I--
LI.I O0
-'
1n~ LU m
W
z
5
ILl
_- 50 to 4o
X--x sPDA-SURVIVORS
n =27
0 - - 0 NO sPDA-SURVIVORS n= 48
x~
~ 3~ 20 t "
IO o
J
o
tO
L8 20
I
R
I
50 40 AGE ( DAYS )
I
t - 5o
50 40 30
o
2o
# 0
9 0
00
9
0
40
5 '0
6 0' 7 ' o
AGE SHUNT SUBSIDED
Fig. 2. Effect of birth weight on survival of infants with sPDA.
80:
n =22 I r =+.77 O=HMD o = non- HMD
60
o ;o 2 '03 0 '
WEIGHT (g)
< ra
70
6o
I , 70
Fig. 3. Proportion of surviving infants with and without sPDA requiring endotracheal intubation and mechanical ventilation related to age they were no longer ventilator dependent.
underwent ligation at age 52 days, and later died with progressive ventilatory failure. Twenty-seven (71%) of the 38 infants with sPDA who received only medical management survived. Survival improved markedly with increasing birth weight (Fig. 2). Outcome was also related to the presence of HMD, but this effect was apparent when only infants with birth weights of 1,250 gm or less were considered. Only 5 (45%) of 11 sPDA infants with HMD and a birth weight _< 1,250 gm survived. In contrast, 11 (69%) of 16 sPDA infants without HMD in this weight range survived. Forty-eight (86%) of the 56 infants without sPDA
Fig. 4. Correlation between age when surviving sPDA infants no longer needed mechanical ventilation through an indwelling endotracheal tube and age of recovery from sPDA. survived. The greater survival of this group could not be attributed solely to lack of a sPDA. Only 8 (14%) of infants without sPDA had HMD, as opposed to 20 (53%) of the 38 infants in the medically managed sPDA group. Also, infants without sPDA tended to be larger, even in this limited birth weight range of 1,500 gm or less. The mean birth weight of medically managed infants with sPDA was 1,095 gm (SD = 227, range 700 to 1,475), and of infants without sPDA was 1,213 gm (SD = 197, range 650 to 1,500). As a group, infants with a prolonged course of hemodynamically important shunting had a lower birth weight than did infants whose clinical evidence of sPDA resolved before 30 days of age ( t - - 3 . 3 8 , P < 0.005). Eleven surviving sPDA infants who were still requiring treatment for congestive heart failure at 30 days of age or longer had an average birth weight of 1,013 gm (SEM = 62). The remaining 16 surviving sPDA infants whose anticongestive treatment could be discontinued before 30 days of age had an average birth weight of 1,259 gm (SEN = 46). Endotracheal intubation and mechanical ventilation for days or weeks was a characteristic need of infants with sPDA (Fig. 3), and the age when this support could finally be withdrawn correlated significantly (P < 0.01) with the age at which clinical evidence of sPDA resolved (Fig. 4). Major complications occurring among surviving infants with and without sPDA are shown in Table I. The principal cause of death for each of the 11 infants with sPDA and 8 infants without sPDA who died is listed in Table I]. These findings are based on autopsy results (11 patients) and terminal clinical events (8 patients).
Volume 92 Number 3 DISCUSSION A left-to-right shunt through the ductus arteriosus is a characteristic feature of HMD. When studied with indicator dilution curves, the shunting has been shown to be present in almost every infant with HMD, typically increasing in magnitude after 36 hours of ageP In this series of low-birth-weight infants of 1,500 gm or less, the shunt became clinically symptomatic in 72% of patients with HMD. The development of a sPDA was not limited to infants with HMD; half of the infants with sPDA did not have HMD. The onset of a clinically detectable ductus shunt coincides in time with the expected decrease of pulmonary vascular resistance. As pulmonary vascular resistance continues to fall, an increasing portion of left ventricular output is diverted through the ductus, whose caliber may equal that of the aorta when viewed by contrast studies or at surgery. Based on shunt calculations taken from catheterization studies of older infants with PDA, ~ a four- or five-fold increase of left ventricular output may have to be sustained to meet the basal need of systemic perfusion while feeding the shunt at the same time. The left ventricle, which in fetal life was accustomed to providing only 1/3of combined ventricular output, ~now must handle up to 4/5 of an immensely increased combined ventricular output. The large diversion of left ventricular output results in a markedly increased pulmonary blood flow which may be delivered at near systemic pressures, since a widely dilated ductus would not be expected to offer substantial resistance. Cardiac catheterization studies have documented elevated pulmonary arterial mean pressures in 14 of 15 preterm infants studied with sPDA. G In another report of infants with sPDA from the same center, the mean pressure difference between the thoracic aorta and pulmonary artery averaged only 6 mm Hg in six infants without respiratory distress syndrome and 9 mm Hg in nine infants who had had respiratory distress syndrome. 7 Preterm lambs with experimental HMD and large left-toright ductus shunts also have elevated pulmonary arterial pressures that are near systemic levels? Presumably, the elevated pulmonary microvascular hydrostatic pressure accompanying the increased blood flow, aggravated by any elevation of left atrial pressure due to cardiac failure, dictates transudation into interstitial spaces." Decreased oncotic pressure due to hypoalbuminemia would further encourage this adverse process. Should capillary permeability be increased in these preterm infants' lungs, which are still undergoing structuraP ~ and biochemicaP 1 maturational changes, there would be an additional tendency for fluid to escape the boundaries of the intravascular compartment.
Medical management of patent ductus arteriosus
471
Table I. Complications among survivors
No. of survivors affected Complication No. of survivors Pulmonary Pneumothorax Interstitial air Infection Chronic respirator lung Hemorrhage Necrotizing enterocolitis Intraventricular hemorrhage Disseminated intravascular coagulation Retrolental fibroplasia Digitalis intoxication
With I Without sPDA sPDA 27
48
2 2 10 3 2 5 2 3 5* 4
2 0 5 0 0 0 0 1 2J 0
*Two with permanentcicatricialchanges. ]'None with permanentcicatricialchanges.
Table lI. Cause of death
Condition With s P D A (11 patients, 7 autopsies)
Without sPDA (8 patients, 4 autopsies)
No. of patients
Age at death (days)
Intraventricular hemorrhage Sepsis (blood culture proven) Obstruction of superior vena cava Pulmonary hemorrhage
4
3,7,5,10
3
24,7,14
2
29,44
2
13,7
Pulmonary hemorrhage Intraventricular hemorrhage Chronic respirator lung Adenovirus pneumonia Presumed cytomegalovirus infection
4
4,5,8,17
1
8
1 1
141 6 59
1
Although the blood volumes of these infants with sPDA were not measured, one would expect that an expanded intravascular volume was necessary to avoid systemic ischemia in the presence of a large ductus run-off. Engorgement of the pulmonary vascular bed exposed to near systemic pressures and dilatation of the left atrium and ventricle would readily account for a substantial increment of volume above a 1.0 kg infant's initial blood volume of 90 to 100 ml measured shortly after birth. 12Any compensation that might occur as a result of fluid retention would lead to dilution of serum proteins and red cell mass. On one hand, the consequent loss of intravascular oncotic pressure would potentiate formation of
472
Cotton et al.
puhnonary edema; on the other, the loss of oxygencarrying capacity per unit volume of blood would place an additional demand on left ventricular output. The concepts of sPDA described in the preceding paragraphs have served as a model on which the protocol for medical management of these infants was based. Constant distending airway pressure was required for all patients with sPDA in order to control pulmonary edema and apnea. Rales, intercostal retraction, and pulmonary infiltrates were abolished or markedly reduced and carbon dioxide retention was usually relieved by a continuous airway pressure of 2 to 6 cm H~O. Premature discontinuation of CDAP was followed by recurring evidence of pulmonary edema and carbon dioxide retention and, on occasion, acute pulmonary hemorrhage. The mechanism of the beneficial effect of CDAP in these infants is unclear. It is tempting to speculate that CDAP reduces ductus flow by producing increased pulmonary vascular resistance. CDAP has been shown to increase pulmonary resistance in experimental animals with normal lungs, la but whether this explains its beneficial effect in infants with sPDA has not been shown. That this is not the case is suggested by the finding that pulmonary vascular resistance in lambs with experimental HMD and large left-to-right ductus shunts is unchanged by CDAP, ~ but extrapolation of this finding to infants whose hyaline membrane disease process has cleared is hazardous. Since CDAP does not appear to reduce lung water content," it has been suggested that when partially collapsed fluid-filled alveoli are expanded, the terminal airway becomes an effective ventilator), unit that is lined by fluid instead of filled with it. Severe apneic spells, often accompanied by bradycardia, were also characteristic of these infants with sPDA. Brief episodes of apnea provided an early clinical warning of pulmonary edema and characteristically decreased in severity and frequency9 when CDAP was initiated or increased. More severe and life-threatening apnea required endotracheal intubation and IPPV with PEEP. That a large left-to-right ductus shunt is a principal cause of ventilator dependence in these infants is supported by the large proportion of them requiring mechanical ventilation well after any early acute pulmonary insufficiency, such as that due to HMD (Fig. 3). This association of ventilatory failure and ductus shunting is substantiated by the strong correlation between the age that IPPV with PEEP was finally discontinued and age that the sPDA resolved (Fig. 4). The age that medical management of sPDA could be discontinued was inversely related to birth weight. T,hise finding, along with the preponderance of sPDA among infants of _< 1,250 gm birth weight, is consistent with gestational age being a determinant of incidence and
The Journal of Pediatrics March 1978
duration of sPDA as well. Evaluation and selection of optimal management approaches, whether medical, surgical, or pharmacologic , must take into consideration the expectation of spontaneous ductus closure within days or weeks, depending on gestational age. The hig h prevalance of pulmonary complications among sPDA infants is not surprising considering the number of these infants requiring prolonged mechanical ventilation. However, the fact that sPDA infants as a group were somewhat smaller and that more had HMD than those without sPDA may have contributed to prolonge d ventilator dependence and may explain the failure of early surgical ligation to reduce ventilator dependence, as reported by other investigators. 1~ The incidence of retrolental fibroplasia and chronic respirator lung disease is noteworthy because these serious complications may be permanently disabling. Protocols designed to assess alternative management approaches should emphasize detection of these and other complications. The morbidity among survivors was predominantly related to therapy and not to the underlying physiologic disturbance. The success of any management protocol will depend heavily on the physicians' and nurses' meticulous attention to detail in Order to minimize iatrogenic complications. Six of the 11 sPDA infants with a fatal outcome had catastrophic hemorrhage into the brain Or lungs occurring within 14 day s after birth. Abnormal clotting function is common among sick preterm infants; TM this should be kept in mind if agents that interfere with platelet function, such as indomethacin, 17 are used. The overriding importance of birth weight as a determinant of outcome is illustrated by the survival of all 11 sPDA infants who weighed more than 1,250 gm. Attempts to document that early ductus closure with surgical or pharmacologic intervention is superior to aggressive medical management alone must be directed toward assessment of morbidity and treatment complications rather than just survival rate. This report is not intended as an endorsement of aggressive medical therapy alone as the superior management approach for infants with sPDA. Whether early ductus closure, with either surgical Or pharmacologic intervention, will lead to improved outcome cannot be determined until carefully controlled studies are conducted that emphasize the natural history of sPDA and the influence of birth weight and HMD. 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.
Volume 92 Number 3
2. 3.
4.
5. 6.
7.
8.
9. 10.
11.
Medical management o f patent ductus arteriosus
Stahlman MT: Recovery from the respiratory distress syndrome, Pediatrics 52:280, 1973. Stahlman MT, Blankenship WJ, Shepard FM, et al: Circulatory studies in clinical hyaline membrane disease, Biol Neonate 20:300, 1972. Rudolph AM, Mayer FE, Nadas AS, et al: Patent ductus arteriosus: A clinical and hemodynamic study of 23 patients in the first year of life, Pediatrics 22:892, 1958. Heymann MA, and Rudolph AM: Control of the ductus arteriosus, Physiol Rev 55:62, 1975. Kitterman JA, Edmunds LH, Gregory GA, et al: Patent ductus arteriosus in premature infants, N Engl J Med 287:473, 1972. Edmunds LH, Gregory GA, HeYmann MA, et al: Surgical closure of the ductus arteriosus in premature infants, Circulation 48:856, 1973. Cotton RB, Lindstrom DP, Kanarek KS, et al: Quantitation of cardiac output components in the presence of bidirectional shunts, J Appl Physiol 43:352, 1977. Staub NC: Pathogenosis of pulmonary edema , Am Rev Resp Dis 109:358, 1974. Stahlman MT: in Moore TD, editor: Lung maturation and the prevention of hyaline membrane disease, report of the Seventieth Ross Conference on Pediatric Research, Columbus, Ohio, 1976, Ross Laboratories, p 15-161 Farrell PM: in Moore TD, editor: Lung maturation and the
12.
13.
14.
15.
16.
17.
473
prevention of hyaline membrane disease, report of the Seventieth Ross Conference on Pediatric Research, Columbus, Ohio , 1976, Ross Laboratories, 1976, pp 28-31. Faxelius G, Raye J, Gutberlet R, Swanstrom S, Tsiantos A, Doianski E, Dehan M, Dyer N, Lindstrom D, Brill, AB, and Stahlman M: Red cell volume measurements and acute blood loss in high risk newborn infants, J PED~ATR 90:273, 1977. Lenfant C, and Howell BJ: Cardiovascular adjustments in dogs during continuous pressure breathing, J Appl Physiol 15:425, 1960. Cotton RB, Lindstrom DP, Kanarek KS, et al: Effect of positive-end-expiratory-pressure on extrapulmonary shunts in exPerimental hyaline membrane disease, Pediatr Res 9:935, 1975. Vidyasagar D, Rajer TNK, Fisher E, et al: Ligation of patent ductus arteriosus in hyaline membrane disease, Pediatr Res 10:319, 1976. Altstatt LB, Dennis LH, Sundell H, et al: Disseminated intravascular coagulation and hyaline membrane disease, Biol Neonate 19:227, 1971. Kocsis JJ, Hernandovich J, Silver MJ, et al: Duration of inhibition of platelet prostaglandin formation and aggregation by ingested aspirin or indomethacin, Prostaglandins 3:141, 1973.
Information for authors
Most of the provisions of the Copyright Act of 1976 became effective on January 1, 1978. Therefore, all manuscripts must be accompanied bY the following statement, signed by each author: "The undersigned author(s) transfers all copyright ownership of the manuscript entitled (title of article) to The C. V. Mosby Company in the event the work is published. The author(s) warrants that the article is original, is not under consideration by another journal, and has not been previously published." Authors will be consulted, when possible, regarding republication of their material.
The Journal o f P E D 1 A T R I C S
467
Medical management of small preterm infants with symptomatic patient ductus arteriosus During 1975, 38 of 44 infants with a birth weight of 0
< o
nIn
LLI n,'-
15 N =38
-1I--
LI.I O0
-'
1n~ LU m
W
z
5
ILl
_- 50 to 4o
X--x sPDA-SURVIVORS
n =27
0 - - 0 NO sPDA-SURVIVORS n= 48
x~
~ 3~ 20 t "
IO o
J
o
tO
L8 20
I
R
I
50 40 AGE ( DAYS )
I
t - 5o
50 40 30
o
2o
# 0
9 0
00
9
0
40
5 '0
6 0' 7 ' o
AGE SHUNT SUBSIDED
Fig. 2. Effect of birth weight on survival of infants with sPDA.
80:
n =22 I r =+.77 O=HMD o = non- HMD
60
o ;o 2 '03 0 '
WEIGHT (g)
< ra
70
6o
I , 70
Fig. 3. Proportion of surviving infants with and without sPDA requiring endotracheal intubation and mechanical ventilation related to age they were no longer ventilator dependent.
underwent ligation at age 52 days, and later died with progressive ventilatory failure. Twenty-seven (71%) of the 38 infants with sPDA who received only medical management survived. Survival improved markedly with increasing birth weight (Fig. 2). Outcome was also related to the presence of HMD, but this effect was apparent when only infants with birth weights of 1,250 gm or less were considered. Only 5 (45%) of 11 sPDA infants with HMD and a birth weight _< 1,250 gm survived. In contrast, 11 (69%) of 16 sPDA infants without HMD in this weight range survived. Forty-eight (86%) of the 56 infants without sPDA
Fig. 4. Correlation between age when surviving sPDA infants no longer needed mechanical ventilation through an indwelling endotracheal tube and age of recovery from sPDA. survived. The greater survival of this group could not be attributed solely to lack of a sPDA. Only 8 (14%) of infants without sPDA had HMD, as opposed to 20 (53%) of the 38 infants in the medically managed sPDA group. Also, infants without sPDA tended to be larger, even in this limited birth weight range of 1,500 gm or less. The mean birth weight of medically managed infants with sPDA was 1,095 gm (SD = 227, range 700 to 1,475), and of infants without sPDA was 1,213 gm (SD = 197, range 650 to 1,500). As a group, infants with a prolonged course of hemodynamically important shunting had a lower birth weight than did infants whose clinical evidence of sPDA resolved before 30 days of age ( t - - 3 . 3 8 , P < 0.005). Eleven surviving sPDA infants who were still requiring treatment for congestive heart failure at 30 days of age or longer had an average birth weight of 1,013 gm (SEM = 62). The remaining 16 surviving sPDA infants whose anticongestive treatment could be discontinued before 30 days of age had an average birth weight of 1,259 gm (SEN = 46). Endotracheal intubation and mechanical ventilation for days or weeks was a characteristic need of infants with sPDA (Fig. 3), and the age when this support could finally be withdrawn correlated significantly (P < 0.01) with the age at which clinical evidence of sPDA resolved (Fig. 4). Major complications occurring among surviving infants with and without sPDA are shown in Table I. The principal cause of death for each of the 11 infants with sPDA and 8 infants without sPDA who died is listed in Table I]. These findings are based on autopsy results (11 patients) and terminal clinical events (8 patients).
Volume 92 Number 3 DISCUSSION A left-to-right shunt through the ductus arteriosus is a characteristic feature of HMD. When studied with indicator dilution curves, the shunting has been shown to be present in almost every infant with HMD, typically increasing in magnitude after 36 hours of ageP In this series of low-birth-weight infants of 1,500 gm or less, the shunt became clinically symptomatic in 72% of patients with HMD. The development of a sPDA was not limited to infants with HMD; half of the infants with sPDA did not have HMD. The onset of a clinically detectable ductus shunt coincides in time with the expected decrease of pulmonary vascular resistance. As pulmonary vascular resistance continues to fall, an increasing portion of left ventricular output is diverted through the ductus, whose caliber may equal that of the aorta when viewed by contrast studies or at surgery. Based on shunt calculations taken from catheterization studies of older infants with PDA, ~ a four- or five-fold increase of left ventricular output may have to be sustained to meet the basal need of systemic perfusion while feeding the shunt at the same time. The left ventricle, which in fetal life was accustomed to providing only 1/3of combined ventricular output, ~now must handle up to 4/5 of an immensely increased combined ventricular output. The large diversion of left ventricular output results in a markedly increased pulmonary blood flow which may be delivered at near systemic pressures, since a widely dilated ductus would not be expected to offer substantial resistance. Cardiac catheterization studies have documented elevated pulmonary arterial mean pressures in 14 of 15 preterm infants studied with sPDA. G In another report of infants with sPDA from the same center, the mean pressure difference between the thoracic aorta and pulmonary artery averaged only 6 mm Hg in six infants without respiratory distress syndrome and 9 mm Hg in nine infants who had had respiratory distress syndrome. 7 Preterm lambs with experimental HMD and large left-toright ductus shunts also have elevated pulmonary arterial pressures that are near systemic levels? Presumably, the elevated pulmonary microvascular hydrostatic pressure accompanying the increased blood flow, aggravated by any elevation of left atrial pressure due to cardiac failure, dictates transudation into interstitial spaces." Decreased oncotic pressure due to hypoalbuminemia would further encourage this adverse process. Should capillary permeability be increased in these preterm infants' lungs, which are still undergoing structuraP ~ and biochemicaP 1 maturational changes, there would be an additional tendency for fluid to escape the boundaries of the intravascular compartment.
Medical management of patent ductus arteriosus
471
Table I. Complications among survivors
No. of survivors affected Complication No. of survivors Pulmonary Pneumothorax Interstitial air Infection Chronic respirator lung Hemorrhage Necrotizing enterocolitis Intraventricular hemorrhage Disseminated intravascular coagulation Retrolental fibroplasia Digitalis intoxication
With I Without sPDA sPDA 27
48
2 2 10 3 2 5 2 3 5* 4
2 0 5 0 0 0 0 1 2J 0
*Two with permanentcicatricialchanges. ]'None with permanentcicatricialchanges.
Table lI. Cause of death
Condition With s P D A (11 patients, 7 autopsies)
Without sPDA (8 patients, 4 autopsies)
No. of patients
Age at death (days)
Intraventricular hemorrhage Sepsis (blood culture proven) Obstruction of superior vena cava Pulmonary hemorrhage
4
3,7,5,10
3
24,7,14
2
29,44
2
13,7
Pulmonary hemorrhage Intraventricular hemorrhage Chronic respirator lung Adenovirus pneumonia Presumed cytomegalovirus infection
4
4,5,8,17
1
8
1 1
141 6 59
1
Although the blood volumes of these infants with sPDA were not measured, one would expect that an expanded intravascular volume was necessary to avoid systemic ischemia in the presence of a large ductus run-off. Engorgement of the pulmonary vascular bed exposed to near systemic pressures and dilatation of the left atrium and ventricle would readily account for a substantial increment of volume above a 1.0 kg infant's initial blood volume of 90 to 100 ml measured shortly after birth. 12Any compensation that might occur as a result of fluid retention would lead to dilution of serum proteins and red cell mass. On one hand, the consequent loss of intravascular oncotic pressure would potentiate formation of
472
Cotton et al.
puhnonary edema; on the other, the loss of oxygencarrying capacity per unit volume of blood would place an additional demand on left ventricular output. The concepts of sPDA described in the preceding paragraphs have served as a model on which the protocol for medical management of these infants was based. Constant distending airway pressure was required for all patients with sPDA in order to control pulmonary edema and apnea. Rales, intercostal retraction, and pulmonary infiltrates were abolished or markedly reduced and carbon dioxide retention was usually relieved by a continuous airway pressure of 2 to 6 cm H~O. Premature discontinuation of CDAP was followed by recurring evidence of pulmonary edema and carbon dioxide retention and, on occasion, acute pulmonary hemorrhage. The mechanism of the beneficial effect of CDAP in these infants is unclear. It is tempting to speculate that CDAP reduces ductus flow by producing increased pulmonary vascular resistance. CDAP has been shown to increase pulmonary resistance in experimental animals with normal lungs, la but whether this explains its beneficial effect in infants with sPDA has not been shown. That this is not the case is suggested by the finding that pulmonary vascular resistance in lambs with experimental HMD and large left-to-right ductus shunts is unchanged by CDAP, ~ but extrapolation of this finding to infants whose hyaline membrane disease process has cleared is hazardous. Since CDAP does not appear to reduce lung water content," it has been suggested that when partially collapsed fluid-filled alveoli are expanded, the terminal airway becomes an effective ventilator), unit that is lined by fluid instead of filled with it. Severe apneic spells, often accompanied by bradycardia, were also characteristic of these infants with sPDA. Brief episodes of apnea provided an early clinical warning of pulmonary edema and characteristically decreased in severity and frequency9 when CDAP was initiated or increased. More severe and life-threatening apnea required endotracheal intubation and IPPV with PEEP. That a large left-to-right ductus shunt is a principal cause of ventilator dependence in these infants is supported by the large proportion of them requiring mechanical ventilation well after any early acute pulmonary insufficiency, such as that due to HMD (Fig. 3). This association of ventilatory failure and ductus shunting is substantiated by the strong correlation between the age that IPPV with PEEP was finally discontinued and age that the sPDA resolved (Fig. 4). The age that medical management of sPDA could be discontinued was inversely related to birth weight. T,hise finding, along with the preponderance of sPDA among infants of _< 1,250 gm birth weight, is consistent with gestational age being a determinant of incidence and
The Journal of Pediatrics March 1978
duration of sPDA as well. Evaluation and selection of optimal management approaches, whether medical, surgical, or pharmacologic , must take into consideration the expectation of spontaneous ductus closure within days or weeks, depending on gestational age. The hig h prevalance of pulmonary complications among sPDA infants is not surprising considering the number of these infants requiring prolonged mechanical ventilation. However, the fact that sPDA infants as a group were somewhat smaller and that more had HMD than those without sPDA may have contributed to prolonge d ventilator dependence and may explain the failure of early surgical ligation to reduce ventilator dependence, as reported by other investigators. 1~ The incidence of retrolental fibroplasia and chronic respirator lung disease is noteworthy because these serious complications may be permanently disabling. Protocols designed to assess alternative management approaches should emphasize detection of these and other complications. The morbidity among survivors was predominantly related to therapy and not to the underlying physiologic disturbance. The success of any management protocol will depend heavily on the physicians' and nurses' meticulous attention to detail in Order to minimize iatrogenic complications. Six of the 11 sPDA infants with a fatal outcome had catastrophic hemorrhage into the brain Or lungs occurring within 14 day s after birth. Abnormal clotting function is common among sick preterm infants; TM this should be kept in mind if agents that interfere with platelet function, such as indomethacin, 17 are used. The overriding importance of birth weight as a determinant of outcome is illustrated by the survival of all 11 sPDA infants who weighed more than 1,250 gm. Attempts to document that early ductus closure with surgical or pharmacologic intervention is superior to aggressive medical management alone must be directed toward assessment of morbidity and treatment complications rather than just survival rate. This report is not intended as an endorsement of aggressive medical therapy alone as the superior management approach for infants with sPDA. Whether early ductus closure, with either surgical Or pharmacologic intervention, will lead to improved outcome cannot be determined until carefully controlled studies are conducted that emphasize the natural history of sPDA and the influence of birth weight and HMD. 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.
Volume 92 Number 3
2. 3.
4.
5. 6.
7.
8.
9. 10.
11.
Medical management o f patent ductus arteriosus
Stahlman MT: Recovery from the respiratory distress syndrome, Pediatrics 52:280, 1973. Stahlman MT, Blankenship WJ, Shepard FM, et al: Circulatory studies in clinical hyaline membrane disease, Biol Neonate 20:300, 1972. Rudolph AM, Mayer FE, Nadas AS, et al: Patent ductus arteriosus: A clinical and hemodynamic study of 23 patients in the first year of life, Pediatrics 22:892, 1958. Heymann MA, and Rudolph AM: Control of the ductus arteriosus, Physiol Rev 55:62, 1975. Kitterman JA, Edmunds LH, Gregory GA, et al: Patent ductus arteriosus in premature infants, N Engl J Med 287:473, 1972. Edmunds LH, Gregory GA, HeYmann MA, et al: Surgical closure of the ductus arteriosus in premature infants, Circulation 48:856, 1973. Cotton RB, Lindstrom DP, Kanarek KS, et al: Quantitation of cardiac output components in the presence of bidirectional shunts, J Appl Physiol 43:352, 1977. Staub NC: Pathogenosis of pulmonary edema , Am Rev Resp Dis 109:358, 1974. Stahlman MT: in Moore TD, editor: Lung maturation and the prevention of hyaline membrane disease, report of the Seventieth Ross Conference on Pediatric Research, Columbus, Ohio, 1976, Ross Laboratories, p 15-161 Farrell PM: in Moore TD, editor: Lung maturation and the
12.
13.
14.
15.
16.
17.
473
prevention of hyaline membrane disease, report of the Seventieth Ross Conference on Pediatric Research, Columbus, Ohio , 1976, Ross Laboratories, 1976, pp 28-31. Faxelius G, Raye J, Gutberlet R, Swanstrom S, Tsiantos A, Doianski E, Dehan M, Dyer N, Lindstrom D, Brill, AB, and Stahlman M: Red cell volume measurements and acute blood loss in high risk newborn infants, J PED~ATR 90:273, 1977. Lenfant C, and Howell BJ: Cardiovascular adjustments in dogs during continuous pressure breathing, J Appl Physiol 15:425, 1960. Cotton RB, Lindstrom DP, Kanarek KS, et al: Effect of positive-end-expiratory-pressure on extrapulmonary shunts in exPerimental hyaline membrane disease, Pediatr Res 9:935, 1975. Vidyasagar D, Rajer TNK, Fisher E, et al: Ligation of patent ductus arteriosus in hyaline membrane disease, Pediatr Res 10:319, 1976. Altstatt LB, Dennis LH, Sundell H, et al: Disseminated intravascular coagulation and hyaline membrane disease, Biol Neonate 19:227, 1971. Kocsis JJ, Hernandovich J, Silver MJ, et al: Duration of inhibition of platelet prostaglandin formation and aggregation by ingested aspirin or indomethacin, Prostaglandins 3:141, 1973.
Information for authors
Most of the provisions of the Copyright Act of 1976 became effective on January 1, 1978. Therefore, all manuscripts must be accompanied bY the following statement, signed by each author: "The undersigned author(s) transfers all copyright ownership of the manuscript entitled (title of article) to The C. V. Mosby Company in the event the work is published. The author(s) warrants that the article is original, is not under consideration by another journal, and has not been previously published." Authors will be consulted, when possible, regarding republication of their material.
