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Congenital diaphragmatic hernia: A persistent problem
EDITOR'S COLUMN
Congenital diaphragmatic hernia: A persistent problem In this issue of the Journal, Bohn et al. 1 and Sakai et al. 2 from The Hospital for Sick Children in Toronto present their extensive experience with neonates born with congenital diaphragmatic hernia as it relates to ventilatory predictors of pulmonary hypoplasia and the effect of surgical repair on respiratory mechanics. Patients were carefully managed with mechanical ventilation and muscle paralysis; the use of other agents, such as narcotics, which might affect the pulmonary vascular bed, is not mentioned. In the article on ventilatory predictors of pulmonary hypoplasia, Bohn et al. present convincing data to support the commonly observed clinical impression that patients with postoperative Paco2 <40 mm Hg and whose lungs are easy to hyperventilate (MAP <20 cm H20, RR <60/min) survive and that nonsurvivors have hypoxemia and hypercarbia (measured in blood samples from a pre--ductus arteriosus site) that cannot be reversed by vigorous hyperventilation (MAP >20 cm H20, RR >60/min). After histologic study of the lungs, interpretation of the morphometric ~ t a indicates that in both the ipsilateral and contralateral lungs there is a similar increase in both the percent of peripheral arteries abnormally muscularized and in the d e g r e e of medial hypertrophy of arteries normally muscularized. The degree o f abnormalities, although significant, is less than that found in a separate study of patients with persistent pulmonary hypertension of the newborn infant) In addition, the ratio of alveoli to arteries is within normal limits, but the total number of alveoli in the ipsilateral lung is severely reduced. The number is also reduced, but to a lesser degree, in the contralateral lung; thus the absolute number of arteries is markedly decreased. The lung volume on both sides is lower than normal. In the accompanying article on the effect of surgical repair on respiratory mechanics, Sakai et al. 2 use an interesting technique to measure compliance of the respiratory system in nine of these patients before and after operation. 4 Seven of the nine had decreased Crs, and those with a decrease of more than 50% subsequently died (four of seven). One infant had no change in Crs, and in one infant Crs increased postoperatively. Mild pulmonary hypoplasia was noted in the latter patient at the time of surgery. In three of the four infants who died, the defect
390
was too large for primary closure, and in the other infant who died the abdomen was so tense after closure of the defect that only the skin was closed. These data confirm the clinical impression that patients with large defects do not do well. In both papers the authors argue that the primary reason for not doing well is pulmonary hypoplasia rather than a reversible elevation of pulmonary vascular resistance. In addition, the negative effect of the decrease in Crs postoperatively complicates the course. To strengthen the position that pulmonary hypoplasia is the predominant abnormality, the authors present evidence from work by lretani, 5 arguing that the primary pathogenic mechanism for the development of congenital diaphragmatic hernia is inhibition of growth of the embryonic lung bud and that the diaphragmatic defect is a secondary phenomenon. They conclude with the intriguing concept previously
See related articles, pp. 423 and 432.
Crs MAP RR
Compliance of respiratory system Mean airway pressure Respiratory rate
stated by Myasaka et al. 6 that there is no need to rush frantically to the operating room and close the defect in these severelY compromised infants at a time when hypoxia and acidosis are most severe. Patients may benefit by a delay, during which medical management with oxygen, mechanical ventilation, pharmacologic agents, fluids, and other supportive measures allow improvement in pulmonary function and decrease in pulmonary vascular resistance. As intriguing and as promising as this approach may be, there are some issues to be considered. Pulmonary hypoplasia as measured by lung volume and weight has been produced experimentally in the fetal sheep 7-9 and fetal rabbit 1~ by creating a defect in the diaphragm through which some of the abdominal contents herniate into the chest and compress the lung and the mediastinal structures. The histologic findings in the ipsilateral lungs in
Volume 111 Number 3
these experiments are consistent with an immature stage of development and coincide with arrested development at the fetal stage when the defect was created. 7,8.1o.. Pulmonary hypoplasia has also been well documented in studies o f newborn infants with congenital diaphragmatic hernia? T M In both the experimental animals s,9,17 and the human infant,13.18-22 right-to-left shunting through a patent ductus arteriosus is a prominent finding. The right-to-left shunt is the result of elevated pulmonary vascular resistance favoring flow through the patent ductus from the pulmonary artery to the aorta. This results in part from pulmonary hypoplasia with hypoxemia and acidosis, causing pulmonary vasoconstriction that may be reversible to some degree. Even if the degree of pulmonary vascular muscular tissue, which is increased by both peripheral extension 16 and medial thickness 1214of muscle, is less than that seen in infants with persistent pulmonary hypertension of the newborn who die (i.e., the most severe cases), it is still enough to cause a physiologically significant decrease in the cross-sectional area of an already small pulmonary vascular bed (for two reasons discussed below) and therefore an increase in pulmonary vascular resistance. The size of the pulmonary vascular bed in infants with congenital diaphragmatic hernia is decreased because of an overall diminution of lung volume (or weight). 1' 129I49t6 In addition, and most important, the number of vessels per unit of lung tissue (even after decreased amount of tissue is accounted for) is diminished, 14 indicating an arrest in the normal development of the lung, which if left uninterrupted would result in an increased number of vessels per unit lung tissuC 3 (i.e., increased density) and therefore a greater cross-sectional area of the pulmonary vascular bed, which is related both to an increase in lung size and to an increase in resistance vessel density. This abnormality, whether assigned to the lung tissue or to the pulmonary vascular bed, becomes the limiting factor in management of these infants. There is enough lung tissue in many of the infants who subsequently die of persistent hypoxemia to eliminate carbon dioxide, as evidenced in the paper by Bohn et al. 1 by the 16 patients in whom severe hypoxemia and hypercarbia developed, along with a ventilatory index >1000, despite postoperative mechanical ventilation. High-frequency oscillation was administered after conventional mechanical ventilation failed. The mean Paco2 decreased from 59 _+ 4 mm Hg with conventional mechanical ventilation to 27 +__2 mm Hg (P <0.001) with high-frequency oscillation. The Pao2 improved from 38 + 6 to 124 ___ 24 mm Hg (P <0.001), as would be expected by the effect of lower Paco2 and diminished respiratory acidosis on partially reversible elevated pulmonary vascular resistance. However, this improvement was maintained
Editor's column
39 1
in only two infants; in 14 others, the Pa02 declined gradually over 24 to 48 hours, and death resulted from increasing hypoxemia and acidosis. This would be the expected course if the diminished size of the pulmonary vascular bed, not the alveolar surface area, was the limiting factor. Starrett and de Lorimier 17in the fetal lamb model of congenital diaphragmatic hernia found that after delivery, when the newborn lambs were given conventional mechanical ventilation, the pulmonary arterial blood pressure remained elevated despite normal Pa02, Pac02, and pH values in the blood on inspired oxygen concentrations from 20% to 100%. This also favors the size of the pulmonary vascular bed, not the area of the alveolar surface, as the limiting factor in survival in these animals with experimentally produced congenital diaphragmatic hernia. When patients who have had a difficult course survived to be examined as children (using the xenon 133 radiospirometry technique), ventilation to the ipsilateral lung was almost always normal (17 of 19), but blood flow to the involved lung was reduced in all patients? 4 Vasodilation of the reversible component of the increased pulmonary vascular resistance has been advocated in newborn infants 13 and tried successfully in some15,z0.21but not all. 14In those infants in whom tolazoline hydrochloride was not successful and who were examined at autopsy (i.e., worst Cases), the reason for the lack of success of pulmonary vasodilator therapy was stated as follows14: In addition to intrapulmonary right-to-left shunting due to alveolar hypoplasia, three anatomic abnormalities of the pulmonary vascular bed resulted in an increase in pulmonary vascular and extrapulmonary right-to-left shunting. These are: (1) a decrease in total size of the pulmonary vascular bed; (2) increased pulmonary arterial smooth muscle; and (3) a decrease in the number of vessels per unit of lung. The elevated pulmonary vascular resistance results in right-to-left shunting through the PDA and the patent foramen ovale (fetal channels). Although the pulmonary arterial resistance vessels had increased smooth muscle, pulmonary vasodilatation as evidenced by an increase in oxygenation could not be documented with the use of tolazoline HCI. This was probably due to severe hypoplasia of the entire pulmonary vascular bed and the decreased number of pulmonary vessels per unit of lung tissue. TM Whether the work presented by Bohn et al. 1and Sakai et al? changes our clinical practice by delaying the time of surgery for newborn infants with congenital diaphragmatic hernia remains to be seen. It certainly is an intriguing idea and has some merit on the basis of the concept that pulmonary hypoplasia, not atelectasis, exists and will not be changed significantly by surgery; thus vigorous medical management of factors affecting the pulmonary vascular
392
Editor's column
bed and resulting in increased pulmonary vascular resistance may improve the chances of the patient tolerating surgery and the adverse mechanical effects of surgery on the chest wall and diaphragm. This approach should be tested by a randomized, prospective protocol that includes concurrent controls to study the effects of pharmacologic agents (paralyzing and narcotic drugs), different modes of ventilation (conventional mechanical ventilation and highfrequency oscillation) and extracorporeal membrane oxygenation on the postoperative course and outcome, and the potential hazards of delaying surgery and of these various modes of intervention. Certainly in the case of extraeorporeal membrane oxygenation, using historical controls as a standard for entry criteria or comparison of success is unacceptable, as shown recently by Dworetz et al. 25 A prospective study would also require that clear criteria for how long to delay surgery or when to go to surgery, based on physiologic variables, be formulated. The work of the Toronto group offers hope that an innovative, carefully considered, prospective, properly controlled approach to the persistent problem of congenital disphragmatic hernia will be forthcoming. Daniel L. Levin, MD Medical Director Pediatric Intensive Care Unit Children's Medical Center Dallas, T X 75235 REFERENCES
1. Bohn D, Tamura M, Perrin D, Barker G, Rabinovitch M. Ventilatory predictors of pulmonary hypoplasia in congenital diaphragmatic hernia, confirmed by morphologicassessment. J PEDIATR1987;111:423-31. 2. Sakai H, Tamura M, Hosokawa Y, Bryan AC, Barker GA, Bohn DJ. Effect of surgical repair on respiratory mechanics in congenital diaphragmatic hernia. J PEDIATR 1987;111: 432-8. 3. Murphy JD, Rabinoviteh M, Goldstein JD, Reid LM. The structural basis of persistent pulmonary hypertension of the newborn infant. J PEDIATR1981;98:962-7. 4. LeSouef PN, England SJ, Bryan AC. Passive respiratory mechanics in newborns and children. Am Rev Respir Dis 1984;129:552-6. 5. Iritani I. Experimental study on embryogenesisof congenital diaphragmatic hernia. Anat Embryol 1984;169:133-9. 6. Miyasaka K, Sankawa H, Nakajo T, Akiyama H. Congenital diaphragmatic hernia: Is emergency radical surgery really necessary? Jpn J Pediatr Surg 1984;16:1417-22. 7. deLorimier AA, Tierney DF, Parker HR. Hypoplastic lungs in fetal lambs with surgically produced congenital diaphragmatic hernia. Surgery 1967;62:12-7. 8. Kent GM, Olley PM, Creighton RE, Dobbinson T, Bryan MH, et al. Hemodynamic and pulmonary changes following
The Journal of Pediatrics September 1987
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10.
11.
12. 13.
14.
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16.
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18.
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surgical creation of a diaphragmatic hernia in fetal lambs. Surgery 1972;72:427-33. Hailer JA, Signer RD, Golladay ES, Inon AE, et al. Pulmonary and ductal hemodynamics in studies of simulated diaphragmatic hernia of fetal and newborn lambs. Baltimore: Johns Hopkins University School of Medicine, 1976. Ohi R, Suzuki H, Kato T, Kasai M. Developmentof the lung in fetal rabbits with experimental diaphragmatic hernia. J Pediatr Surg 1976;11:955-9. deLorimier AA, Manus AG, Tyler WS. Morphometry of normal and hypoplastic lungs in newborn Iambs. Curr Topics Surg Res 1969;1:431-42. Kitagawa M, Hislop A, Boyden EA, Reid L. Br J Surg 1971;58:342-6. Naeye RL, Shochat SJ, Whitman V, Maisels MJ. Unsuspected pulmonary vascular abnormalities associated with diaphragmatic hernia. Pediatrics 1976;58:902-6. Levin DL. Morphologic analysis of the pulmonary vascular bed in congenital left-sided diaphragmatic hernia. J PEDXATR 1978;92:805-9. Bloss RS, Turmen T, Beardmore HE, Aranda JV. Tolazoline therapy for persistent pulmonary hypertension after congenital diaphragmatic hernia repair. J PEDIATR1980;97:984-8. Geggel RL, Murphy JD, Langleben D, Crone RK, et al. Congenital diaphragmatic hernia: arterial structural changes and persistent pulmonary hypertension after surgical repair. J PEDIATR1985;107:457-64. Starrett RW, deLorimier AA. Congenital diaphragmatic hernia in lambs: hemodynamic and ventilatory changes with breathing. J Pediatr Surg 1975;10:575-80. Rowe MI, Uribe FL. Diaphragmatic hernia in the newborn infant: blood gas and pH considerations. Surgery 1971; 70:758-61. Boix-Ochoa J, Peguero G, Seijo G, Natal A, Canals J. Acid-base balance and blood gases in prognosis and therapy of congenital diaphragmatic hernia. J Pediatr Surg 1974; 9:49-57. Maisels MJ, Shoehat SJ, Friedman Z, Whitman V, Naeye RL. Pulmonary vascular resistance in diaphragmatic hernia: response to tolazoline. Pediatr Res 1976;10:427. Levy RJ, Rosenthal A, Freed MD, Smith CH, et al. Persistent pulmonary hypertension in a newborn with congenital diaphragmatic hernia: successful management with tolazoline. Pediatrics 1977;60:740-2. Vacanti JP, Crone RK, Murphy JD, Smith SD, et al. The pulmonary hemodynamicresponse to perioperative anesthesia in the treatment of high-risk infants with congenital diaphragmatic hernia. J Pediatr Surg 1984;19:672-8. Levin DL, Rudolph AM, Heymann MA, Phibbs RH. Morphological developmentof the pulmonary vascular bed in fetal lambs. Circulation 1976;53:144-51. Wohl MEB, Griscom NT, Strieder DJ, et al. The lung followingrepair of congenital diaphragmatic hernia. J PEDIATR 1977;90:405-14. Dworetz AR, Moya FR, Sabo B, Gross I. Survival in infants with persistent pulmonary hypertension (PPHN) without extracorporeal membrane oxygenation (ECMO). Pediatr Res 1987;21:360A.
Congenital diaphragmatic hernia: A persistent problem In this issue of the Journal, Bohn et al. 1 and Sakai et al. 2 from The Hospital for Sick Children in Toronto present their extensive experience with neonates born with congenital diaphragmatic hernia as it relates to ventilatory predictors of pulmonary hypoplasia and the effect of surgical repair on respiratory mechanics. Patients were carefully managed with mechanical ventilation and muscle paralysis; the use of other agents, such as narcotics, which might affect the pulmonary vascular bed, is not mentioned. In the article on ventilatory predictors of pulmonary hypoplasia, Bohn et al. present convincing data to support the commonly observed clinical impression that patients with postoperative Paco2 <40 mm Hg and whose lungs are easy to hyperventilate (MAP <20 cm H20, RR <60/min) survive and that nonsurvivors have hypoxemia and hypercarbia (measured in blood samples from a pre--ductus arteriosus site) that cannot be reversed by vigorous hyperventilation (MAP >20 cm H20, RR >60/min). After histologic study of the lungs, interpretation of the morphometric ~ t a indicates that in both the ipsilateral and contralateral lungs there is a similar increase in both the percent of peripheral arteries abnormally muscularized and in the d e g r e e of medial hypertrophy of arteries normally muscularized. The degree o f abnormalities, although significant, is less than that found in a separate study of patients with persistent pulmonary hypertension of the newborn infant) In addition, the ratio of alveoli to arteries is within normal limits, but the total number of alveoli in the ipsilateral lung is severely reduced. The number is also reduced, but to a lesser degree, in the contralateral lung; thus the absolute number of arteries is markedly decreased. The lung volume on both sides is lower than normal. In the accompanying article on the effect of surgical repair on respiratory mechanics, Sakai et al. 2 use an interesting technique to measure compliance of the respiratory system in nine of these patients before and after operation. 4 Seven of the nine had decreased Crs, and those with a decrease of more than 50% subsequently died (four of seven). One infant had no change in Crs, and in one infant Crs increased postoperatively. Mild pulmonary hypoplasia was noted in the latter patient at the time of surgery. In three of the four infants who died, the defect
390
was too large for primary closure, and in the other infant who died the abdomen was so tense after closure of the defect that only the skin was closed. These data confirm the clinical impression that patients with large defects do not do well. In both papers the authors argue that the primary reason for not doing well is pulmonary hypoplasia rather than a reversible elevation of pulmonary vascular resistance. In addition, the negative effect of the decrease in Crs postoperatively complicates the course. To strengthen the position that pulmonary hypoplasia is the predominant abnormality, the authors present evidence from work by lretani, 5 arguing that the primary pathogenic mechanism for the development of congenital diaphragmatic hernia is inhibition of growth of the embryonic lung bud and that the diaphragmatic defect is a secondary phenomenon. They conclude with the intriguing concept previously
See related articles, pp. 423 and 432.
Crs MAP RR
Compliance of respiratory system Mean airway pressure Respiratory rate
stated by Myasaka et al. 6 that there is no need to rush frantically to the operating room and close the defect in these severelY compromised infants at a time when hypoxia and acidosis are most severe. Patients may benefit by a delay, during which medical management with oxygen, mechanical ventilation, pharmacologic agents, fluids, and other supportive measures allow improvement in pulmonary function and decrease in pulmonary vascular resistance. As intriguing and as promising as this approach may be, there are some issues to be considered. Pulmonary hypoplasia as measured by lung volume and weight has been produced experimentally in the fetal sheep 7-9 and fetal rabbit 1~ by creating a defect in the diaphragm through which some of the abdominal contents herniate into the chest and compress the lung and the mediastinal structures. The histologic findings in the ipsilateral lungs in
Volume 111 Number 3
these experiments are consistent with an immature stage of development and coincide with arrested development at the fetal stage when the defect was created. 7,8.1o.. Pulmonary hypoplasia has also been well documented in studies o f newborn infants with congenital diaphragmatic hernia? T M In both the experimental animals s,9,17 and the human infant,13.18-22 right-to-left shunting through a patent ductus arteriosus is a prominent finding. The right-to-left shunt is the result of elevated pulmonary vascular resistance favoring flow through the patent ductus from the pulmonary artery to the aorta. This results in part from pulmonary hypoplasia with hypoxemia and acidosis, causing pulmonary vasoconstriction that may be reversible to some degree. Even if the degree of pulmonary vascular muscular tissue, which is increased by both peripheral extension 16 and medial thickness 1214of muscle, is less than that seen in infants with persistent pulmonary hypertension of the newborn who die (i.e., the most severe cases), it is still enough to cause a physiologically significant decrease in the cross-sectional area of an already small pulmonary vascular bed (for two reasons discussed below) and therefore an increase in pulmonary vascular resistance. The size of the pulmonary vascular bed in infants with congenital diaphragmatic hernia is decreased because of an overall diminution of lung volume (or weight). 1' 129I49t6 In addition, and most important, the number of vessels per unit of lung tissue (even after decreased amount of tissue is accounted for) is diminished, 14 indicating an arrest in the normal development of the lung, which if left uninterrupted would result in an increased number of vessels per unit lung tissuC 3 (i.e., increased density) and therefore a greater cross-sectional area of the pulmonary vascular bed, which is related both to an increase in lung size and to an increase in resistance vessel density. This abnormality, whether assigned to the lung tissue or to the pulmonary vascular bed, becomes the limiting factor in management of these infants. There is enough lung tissue in many of the infants who subsequently die of persistent hypoxemia to eliminate carbon dioxide, as evidenced in the paper by Bohn et al. 1 by the 16 patients in whom severe hypoxemia and hypercarbia developed, along with a ventilatory index >1000, despite postoperative mechanical ventilation. High-frequency oscillation was administered after conventional mechanical ventilation failed. The mean Paco2 decreased from 59 _+ 4 mm Hg with conventional mechanical ventilation to 27 +__2 mm Hg (P <0.001) with high-frequency oscillation. The Pao2 improved from 38 + 6 to 124 ___ 24 mm Hg (P <0.001), as would be expected by the effect of lower Paco2 and diminished respiratory acidosis on partially reversible elevated pulmonary vascular resistance. However, this improvement was maintained
Editor's column
39 1
in only two infants; in 14 others, the Pa02 declined gradually over 24 to 48 hours, and death resulted from increasing hypoxemia and acidosis. This would be the expected course if the diminished size of the pulmonary vascular bed, not the alveolar surface area, was the limiting factor. Starrett and de Lorimier 17in the fetal lamb model of congenital diaphragmatic hernia found that after delivery, when the newborn lambs were given conventional mechanical ventilation, the pulmonary arterial blood pressure remained elevated despite normal Pa02, Pac02, and pH values in the blood on inspired oxygen concentrations from 20% to 100%. This also favors the size of the pulmonary vascular bed, not the area of the alveolar surface, as the limiting factor in survival in these animals with experimentally produced congenital diaphragmatic hernia. When patients who have had a difficult course survived to be examined as children (using the xenon 133 radiospirometry technique), ventilation to the ipsilateral lung was almost always normal (17 of 19), but blood flow to the involved lung was reduced in all patients? 4 Vasodilation of the reversible component of the increased pulmonary vascular resistance has been advocated in newborn infants 13 and tried successfully in some15,z0.21but not all. 14In those infants in whom tolazoline hydrochloride was not successful and who were examined at autopsy (i.e., worst Cases), the reason for the lack of success of pulmonary vasodilator therapy was stated as follows14: In addition to intrapulmonary right-to-left shunting due to alveolar hypoplasia, three anatomic abnormalities of the pulmonary vascular bed resulted in an increase in pulmonary vascular and extrapulmonary right-to-left shunting. These are: (1) a decrease in total size of the pulmonary vascular bed; (2) increased pulmonary arterial smooth muscle; and (3) a decrease in the number of vessels per unit of lung. The elevated pulmonary vascular resistance results in right-to-left shunting through the PDA and the patent foramen ovale (fetal channels). Although the pulmonary arterial resistance vessels had increased smooth muscle, pulmonary vasodilatation as evidenced by an increase in oxygenation could not be documented with the use of tolazoline HCI. This was probably due to severe hypoplasia of the entire pulmonary vascular bed and the decreased number of pulmonary vessels per unit of lung tissue. TM Whether the work presented by Bohn et al. 1and Sakai et al? changes our clinical practice by delaying the time of surgery for newborn infants with congenital diaphragmatic hernia remains to be seen. It certainly is an intriguing idea and has some merit on the basis of the concept that pulmonary hypoplasia, not atelectasis, exists and will not be changed significantly by surgery; thus vigorous medical management of factors affecting the pulmonary vascular
392
Editor's column
bed and resulting in increased pulmonary vascular resistance may improve the chances of the patient tolerating surgery and the adverse mechanical effects of surgery on the chest wall and diaphragm. This approach should be tested by a randomized, prospective protocol that includes concurrent controls to study the effects of pharmacologic agents (paralyzing and narcotic drugs), different modes of ventilation (conventional mechanical ventilation and highfrequency oscillation) and extracorporeal membrane oxygenation on the postoperative course and outcome, and the potential hazards of delaying surgery and of these various modes of intervention. Certainly in the case of extraeorporeal membrane oxygenation, using historical controls as a standard for entry criteria or comparison of success is unacceptable, as shown recently by Dworetz et al. 25 A prospective study would also require that clear criteria for how long to delay surgery or when to go to surgery, based on physiologic variables, be formulated. The work of the Toronto group offers hope that an innovative, carefully considered, prospective, properly controlled approach to the persistent problem of congenital disphragmatic hernia will be forthcoming. Daniel L. Levin, MD Medical Director Pediatric Intensive Care Unit Children's Medical Center Dallas, T X 75235 REFERENCES
1. Bohn D, Tamura M, Perrin D, Barker G, Rabinovitch M. Ventilatory predictors of pulmonary hypoplasia in congenital diaphragmatic hernia, confirmed by morphologicassessment. J PEDIATR1987;111:423-31. 2. Sakai H, Tamura M, Hosokawa Y, Bryan AC, Barker GA, Bohn DJ. Effect of surgical repair on respiratory mechanics in congenital diaphragmatic hernia. J PEDIATR 1987;111: 432-8. 3. Murphy JD, Rabinoviteh M, Goldstein JD, Reid LM. The structural basis of persistent pulmonary hypertension of the newborn infant. J PEDIATR1981;98:962-7. 4. LeSouef PN, England SJ, Bryan AC. Passive respiratory mechanics in newborns and children. Am Rev Respir Dis 1984;129:552-6. 5. Iritani I. Experimental study on embryogenesisof congenital diaphragmatic hernia. Anat Embryol 1984;169:133-9. 6. Miyasaka K, Sankawa H, Nakajo T, Akiyama H. Congenital diaphragmatic hernia: Is emergency radical surgery really necessary? Jpn J Pediatr Surg 1984;16:1417-22. 7. deLorimier AA, Tierney DF, Parker HR. Hypoplastic lungs in fetal lambs with surgically produced congenital diaphragmatic hernia. Surgery 1967;62:12-7. 8. Kent GM, Olley PM, Creighton RE, Dobbinson T, Bryan MH, et al. Hemodynamic and pulmonary changes following
The Journal of Pediatrics September 1987
9.
10.
11.
12. 13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
surgical creation of a diaphragmatic hernia in fetal lambs. Surgery 1972;72:427-33. Hailer JA, Signer RD, Golladay ES, Inon AE, et al. Pulmonary and ductal hemodynamics in studies of simulated diaphragmatic hernia of fetal and newborn lambs. Baltimore: Johns Hopkins University School of Medicine, 1976. Ohi R, Suzuki H, Kato T, Kasai M. Developmentof the lung in fetal rabbits with experimental diaphragmatic hernia. J Pediatr Surg 1976;11:955-9. deLorimier AA, Manus AG, Tyler WS. Morphometry of normal and hypoplastic lungs in newborn Iambs. Curr Topics Surg Res 1969;1:431-42. Kitagawa M, Hislop A, Boyden EA, Reid L. Br J Surg 1971;58:342-6. Naeye RL, Shochat SJ, Whitman V, Maisels MJ. Unsuspected pulmonary vascular abnormalities associated with diaphragmatic hernia. Pediatrics 1976;58:902-6. Levin DL. Morphologic analysis of the pulmonary vascular bed in congenital left-sided diaphragmatic hernia. J PEDXATR 1978;92:805-9. Bloss RS, Turmen T, Beardmore HE, Aranda JV. Tolazoline therapy for persistent pulmonary hypertension after congenital diaphragmatic hernia repair. J PEDIATR1980;97:984-8. Geggel RL, Murphy JD, Langleben D, Crone RK, et al. Congenital diaphragmatic hernia: arterial structural changes and persistent pulmonary hypertension after surgical repair. J PEDIATR1985;107:457-64. Starrett RW, deLorimier AA. Congenital diaphragmatic hernia in lambs: hemodynamic and ventilatory changes with breathing. J Pediatr Surg 1975;10:575-80. Rowe MI, Uribe FL. Diaphragmatic hernia in the newborn infant: blood gas and pH considerations. Surgery 1971; 70:758-61. Boix-Ochoa J, Peguero G, Seijo G, Natal A, Canals J. Acid-base balance and blood gases in prognosis and therapy of congenital diaphragmatic hernia. J Pediatr Surg 1974; 9:49-57. Maisels MJ, Shoehat SJ, Friedman Z, Whitman V, Naeye RL. Pulmonary vascular resistance in diaphragmatic hernia: response to tolazoline. Pediatr Res 1976;10:427. Levy RJ, Rosenthal A, Freed MD, Smith CH, et al. Persistent pulmonary hypertension in a newborn with congenital diaphragmatic hernia: successful management with tolazoline. Pediatrics 1977;60:740-2. Vacanti JP, Crone RK, Murphy JD, Smith SD, et al. The pulmonary hemodynamicresponse to perioperative anesthesia in the treatment of high-risk infants with congenital diaphragmatic hernia. J Pediatr Surg 1984;19:672-8. Levin DL, Rudolph AM, Heymann MA, Phibbs RH. Morphological developmentof the pulmonary vascular bed in fetal lambs. Circulation 1976;53:144-51. Wohl MEB, Griscom NT, Strieder DJ, et al. The lung followingrepair of congenital diaphragmatic hernia. J PEDIATR 1977;90:405-14. Dworetz AR, Moya FR, Sabo B, Gross I. Survival in infants with persistent pulmonary hypertension (PPHN) without extracorporeal membrane oxygenation (ECMO). Pediatr Res 1987;21:360A.