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Pathophysiology of congenital diaphragmatic hernia III: Exogenous surfactant therapy for the high-risk neonate with CDH
Pathophysiology Exogenous Surfactant
of Congenital Diaphragmatic Hernia III: Therapy for the High-Risk Neonate With CDH
By Philip L. Glick, Corinne L. Leach, Gail E. Besner, Edmund A. Egan, Frederick C. Morin, Anna Malanowska-Kantoch,
Luther K. Robinson, Alan Brody, Amol S. Lele, Margaret McDonnell, Bruce Holm,
Brian T. Rodgers, Michael E. Msall, Norman G. Courey, Melvin P. Karp, James E. Allen, Theodore C. Jewett, Jr, and Donald R. Cooney Buffalo, l Exogenous surfactant therapy (EST) in surfactantdeficient premature infants has been shown to improve lung compliance, decrease morbidity, and improve survival. Reports have demonstrated that newborns with congenital diaphragmatic hernia (CDH) have lung compliance, pressurevolume curves, and hyaline membrane formation resembling those changes seen in surfactant deficient premature newborns. We hypothesize that EST may also benefit infants with CDH. All high risk cases of prenatally diagnosed CDH at Children’s Hospital of Buffalo from November 1988 to February 1991 were prospectively evaluated for EST. In those families who chose to participate, the surfactant preparation, lnfasurf (100 mg/kg), was instilled into the newborn’s lungs prior to the first breath. The remainder of the perinatal, neonatal, and surgical care was performed in a routine manner. Three high-risk prenatally diagnosed newborns with left CDH were treated with EST. All showed signs of decreased pulmonary compliance. but could still be adequately oxygenated and ventilated. Surgical correction was performed after stabilization and all required patch closures. Two of the three infants suffered no life-threatening episodes of pulmonary hypertension and all survived. These infants had many known indicators for poor outcome in CDH with an expected survival of less than 20%. We believe that EST in these neonates with CDH contributed to their survival with minimum morbidity. These results suggest that surfactant replacement for the high-risk neonate with CDH warrants further consideration and a randomized clinical trial is being planned. Copyright Q 1992 by W.B. Saunders Company
INDEX WORDS: Congenital diaphragmatic replacement, therapy.
surfactant
therapy,
prenatal
hernia, surfactant diagnosis, fetal
From The Buffalo Institute of Fetal Therapy, the Children’s Hospital of Buffalo Perinatal Center, and the Departments of Surgery, Pediatrics, Radiology, and Obstetrics/Gynecology, School of Medicine and Biomedical Sciences, The University at Buffalo, State Universiv of New York, The Children’s Hospital of Buffalo, Buffalo, NY: Suppotted in part by The Women’s and Children’s Health Research Foundation of the Children’s Hospital of Buffalo, and BSRGIRDF Award, State University of New York at Buffalo. Presented at the 38th Annual International Congress of the British Association of Paediatn’c Surgeons, Budapest, Hungary, July 24-26, 1991. Address reprint requests to Philip L. Glick, MD, The Buffalo Institute of Fetal Therapy, The Children’s Hospital of Buffalo, 219 Byant St, Buffalo, NY 14222. Copyright o 1992 by WB. Saunders Company 0022-3468/92/2707-0020$03.~fO
066
New York
T
HE MORTALITY for congenital diaphragmatic hernia (CDH) remains between 50% and 88%.1-5 The high mortality in these infants has been attributed to the combination of pulmonary hypoplasia and pulmonary hypertension (pH).l~~-lOIn addition, studies in animal models and clinical reports have demonstrated that newborns with CDH have lung compliance, pressure-volume curves, and hyaline membrane formation resembling those changes seen in surfactant-deficient premature newborns.“-l3 Again, similar to premature newborns, amniotic fluid (AF) analysis has shown that full-term fetuses with prenatally diagnosed CDH have immature AF lecithinsphingomyelin (L/S) ratios and absent AF phosphatidylglycerol (PG). 14-17Exogenous surfactant therapy (EST) in premature infants with immature L/S ratios and absent PG has been shown to improve lung compliance, decrease morbidity, and improve survival.18 If the in utero mechanical effects of the herniated viscera in the chest of the fetus with CDH, which cause the pulmonary hypoplasia and PH, also result in a quantitative or functional surfactant deficiency, then it is possible to hypothesize that EST might also benefit infants with CDH. With this rationale in mind, we have recently cared for three newborns with prenatally diagnosed CDH, and treated them with EST. MATERIALS AND METHODS All high-risk cases (n = 3) of prenatally diagnosed CDH at Children’s Hospital of Buffalo from November 1988 to February 1991 were evaluated by our fetal therapy team (BIFT) and all the therapeutic options, ie, fetal surgery, maternal transport to a neonatal extracorporeal membrane oxygenation (ECMO) center, high-frequency ventilation, EST, or routine management, were considered. High risk was defined as those CDH diagnosed prenatally with associated polyhydramnios, dilated stomach in the chest, and the heart and mediastinum shifted to the contralateral chest wall.‘~4~19~u’ In the families who chose EST and after informed consent was given, Infasurf (100 mgikg; Ony Inc, Amherst, NY) was instilled into the newborn’s lungs via the endotracheal tube (ET) prior to the first breath. Infasurf is a calf lung surfactant extract used routinely in our intensive care nursery for the prevention/treatment of hyaline membrane disease in premature infants. The remainder of the perinatal, neonatal, and surgical care was performed in a routine manner.
JournalofPediatricSurgery,
Vol27, No 7 (July), 1992: pp
886-869
EXOGENOUS
SURFACTANT
867
THERAPY FOR CDH
Case Reports Case 1. A 35year-old woman (Gl, PO) was noted to have a size versus dates discrepancy in her fundal height at 35 weeks’ gestation. A level II obstetrical ultrasound examination showed the fetus to have a left CDH associated with polyhydramnios, dilated stomach in the chest, and the heart and mediastinum shifted to the right lateral chest wall. Amniocentesis for karyotype analysis showed 46,Xx. The family was referred to BIFT, the parents were counseled, and the options for care were outlined. The theoretical feasibility of surfactant replacement for this high-risk newborn was explained to the parents and they requested that we proceed. A 3.2-kg female was delivered at term, via a vaginal delivery. Infasurf was instilled via the ET into the lungs prior to the first breath. Hand ventilation with peak inspiratoty pressures (PIP) of 50 cm HzO, positive end-expiratory pressures (PEEP) of 4 cm HzO, and a rate of 60 breaths/min was required to generate a tidal volume sufficient to move the chest wall adequately. A nasogastric tube was placed. The infant was paralyzed (pancuronium, 0.1 mglkgih, intravenously [IV], as needed), sedated (fentanyl, 10 kg/kg/h, IV), and alkalinized (sodium bicarbonate, 1 mEq/kg/h, IV, and hyperventilation) to keep pH > 7.5 and PC02 25 to 30 mm Hg. The best preoperative, postductal arterial blood gas (ABG) (FIOz = lOO%, PIP = 40, PEEP = 2, mean airway pressure [MAP] = 17, rate = 60, and ventilatory index [VI] = 1,020) was 7.44/28/144/-4 (pHIPCOs/POJbase excess). A chest tube was inserted to treat a right pneumothorax. The infant was taken to the operating room at 3 hours of life and via a left subcostal approach, the stomach, the spleen, the entire small bowel, and a majority of the colon were found to have herniated through a 6 x 2 cm defect in the left diaphragm. A small airless left lung was noted. The hernia required a polytetrafluoroethylene (PTFE) patch to facilitate closure. A left chest tube was placed to 5 cm Hz0 water seal. In the first 24 hours postoperatively, representative simultaneous preductal and postductal ABGs (FIOz = 72%, PIP = 24, PEEP = 2, MAP = 10, rate = 45, VI = 450) were 7.51/24/278/-2 and 7.51/26/177/-2, respectively. On day of life 3, the paralysis was discontinued. Subsequently, the pH was allowed to normalize. The infant was weaned from the ventilator as tolerated and extubated on day 18. During this period the infant suffered no life-threatening episodes of PH. She was discharged home on day 41. The child shows no signs of chronic pulmonary disease. Neurodevelopmental follow-up at 35 months of age is normal. Case 2. A 35-year-old woman (Gl, PO) underwent routine ultrasound and amniocentesis (46,Xx) at 17 weeks’ gestation; ultrasound suggested a left CDH. At 29 weeks’ gestation the patient was referred to BIFI and the diagnosis of a left CDH with polyhydramnios, dilated stomach in the chest, with the heart and mediastinum shifted to the right was confirmed. The therapeutic options were explained and the family requested EST. At 31 weeks’ gestation, premature rupture of membranes (PROM) occurred. The mother was given betamethasone (9 mg/d, intramuscularly [IM]) and cesarean section was performed 48 hours later. A 2.09-kg female was delivered. Infasurf was instilled via the ET. The infant was paralyzed, sedated, alkalinized, and ventilated as described previously. Preoperatively, representative preductal and postductal ABGs (FI02 = lOO%, PIP = 25, PEEP = 3, rate = 82, VI = 820) were 7.51/29/493/ + 1 and 7.461311 67/+3 and measured compliance by an on-line pulmonary function computer (Pulmonary Evaluation and Diagnostic System [PEDS]; MAS Inc, Philadelphia, PA) was 0.23 mL/cm HzOlkg (normal, > 2.0 mL/cm HzOlkg). At 5 hours of age, the patient underwent an uneventful PTFE patch closure of the CDH and Ladd’s procedure.
For the first 96 hours postoperatively, the patient had persistent, but not life-threatening, PH with representative preductal and postductal ABGs (FIOr = 90%, PIP = 19, PEEP = 2. rate = 90) of 7.55/37/260/+9 and 7.55/34/107/+10. The paralysis was discontinued on day 2. The ventilator was gradually weaned, but on day 17 a repeat cardiac echo was performed because of failure to progress toward extubation. This showed a patent ductus arteriosus (PDA) with bidirectional shunting. On day 21 a PDA ligation was performed and the child was successfully extubated on day 31. The child underwent a Nissen fundoplication on day 42. The patient was discharged to home on day 63. This child shows no signs of chronic pulmonary disease and neurodevelopmental follow-up at 22 months is normal. Case 3. A 33-year-old woman (Gl, PO) underwent ultrasound at 28 weeks’ gestation showing a twin pregnancy. Twin A (46,XY) was normal, and twin B (46,Xx) was found to have a left CDH with polyhydramnios, dilated stomach in the chest, with the heart and mediastinum shifted to the right. The patient was referred to BIFT, and the therapeutic options were discussed with the family. EST for twin B in the delivery room was planned. PROM of twin A occurred at 33 weeks’ gestation. Amniocentesis results showed twin B to have an immature L/S ratio (1.2) and a negative PG. There was insufficient AF surrounding twin A to sample. The mother was treated with betamethasone (12 mg, IM) and underwent emergency cesarean section 8 hours later when the leg of twin A prolapsed. Twin A weighed 2.1 kg and had an uneventful delivery. Twin B weighed 1.7 kg and Infasurf was instilledvia the ET. The infant received cardiopulmonary resuscitation for several minutes in the delivery room because of persistent bradycardia. The baby was paralyzed, sedated, alkalinized, and ventilated as previously described. Preoperative representative preductal and postductal ABGs (FlOr = lOO%, PIP = 23. PEEP = 3, rate = 90, VI = 1,170) were 7.4013311551-3 and 7.341 40/95/ -4 and measured compliance by the PEDS was 0.22 mL/cm HzO/kg. At 3 hours of age the baby underwent an uneventful PTFE patch closure of the CDH. The patient did well for the first 15 hours postoperatively. Subsequently, she developed life-threatening PH with representative preductal and postductal ABGs (FIO;! = lOO%, PIP = 24, PEEP = 3, rate = 90) of 7.56/26/3561+3 and 7.36/54/35/+4. Cardiac echo showed decreased cardiac contractility with significant right-to-left shunt through a PDA. Prematurity and small size precluded consideration of ECMO. Severe PH persisted for the next 8 hours and then resolved. On day 3 alkalinization and paralysis were stopped. Ventilatory support was gradually weaned. On day 29 she was returned to the operating room for lysis of adhesions and a Ladd’s procedure. Extubation was accomplished on day 40. On day 70 she underwent a Nissen fundoplication. On day 97 she was discharged to home on bronchodilators and l/8 Llmin of 02, which were both subsequently stopped. Neurodevelopmental follow-up at 12 months is significant for a partial hearing loss as demonstrated by brain stem auditory evoked responses. The patient is being followed closely by our developmental and rehabilitation center. DISCUSSION These infants had many known high-risk factors for a poor prognosis in CDH, eg, prenatal diagnosis, polyhydramnios, dilated stomach in the chest, mediastinal shift, contralateral pneumothorax, VI > 1,000, and patch closure of the defect, with an expected survival of less than 20%.134J9-21EST may have re-
866
GLICK ET AL
duced surface tension and stabilized functional residual capacity in the hypoplastic lungs resulting in improved lung compliance, decreased barotrauma, enhanced pulmonary blood flow and gas exchange; may have prevented or limited barotrauma, which can cause life-threatening episodes of PH; and may have contributed to their survival with minimal morbidity. Respiratory distress syndrome (RDS) is caused by a surfactant deficiency, due to a decrease in surfactant synthesis or release by the alveolar type II pneumocyte.22,23 Kwong et al have shown in doubleblind, clinical human trials that EST prevents RDS in premature newborns and allows inspired oxygen, MAP, ventilator rate, and VI to be lower in the treated group during the first 48 hours of life when compared with untreated controls.18 In addition, there was an improved survival and lower morbidity in the surfactant-treated group. Most recently, Auten et al reported the efficacy of EST in 14 full-term neonates with respiratory failure.24 When compared with pretreatment parameters, all of their patients showed improvement in arterial-alveolar oxygenation ratio, oxygenation index, and chest radiographs. All patients survived and none required chronic oxygenation therapy. A surfactant deficiency contributing to the pathophysiology of CDH has been considered. Wigglesworth et al have reported that by histological, morphological, and quantitative biochemical criteria, the fetus/newborn with CDH shows many similarities to the premature, surfactant-deficient newborn with RDS.12 Pringle et al, using a fetal CDH lamb model, studied pulmonary maturity and morphology at various stages of gestation with electronmicroscopy.2,26 They showed that there was an increase in number and size of the type II pneumocyte, that these changes affected the ipsilateral greater than the contralateral lung, and that these changes were partially reversed by in utero CDH repair. No type II pneumocyte functional studies or surfactant analyses were performed. Full-term fetuses with prenatally diagnosed CDH have been found to have immature AF L/S ratios and absent AF PG, findings similar to premature surfactant-deficient newborns.14-I7 The present case 3 (twin B) had documented surfactantdeficient lungs (PG negative, L/S = 1.3), but because of twin A’s PROM, it is not clear whether the CDH and/or prematurity were the contributing factors. Additionally, data from our laboratory have con-
firmed a surfactant deficiency in the fetal lamb CDH mode1.27 In the unventilated CDH newborns at term, total lung lavage phospholipids were significantly different in quantity as well as composition when compared to controls. Type II pneumocyte synthesis of phosphatidylcholine was also decreased when compared with controls. These studies documenting a surfactant deficiency in the fetal lamb CDH model suggest that a similar pathophysiology may also be occurring in humans with CDH. Harrison’s pioneering work in fetal animal CDH preparations and human fetuses has been the benchmark of excellence and has provided the rationale for in utero correction of CDH.11,28-33The concept of EST in the high-risk newborn with CDH builds on many of these past accomplishments, but takes a different, perhaps more practical approach to the high-risk fetus/newborn with CDH. Even if Harrison’s proposed prospective human clinical trials demonstrate the efficacy of in utero CDH repair, the vast majority of the hundreds of newborns affected per year with CDH will not be able to take advantage of this treatment modality for obvious practical and ethical reasons.33 EST, which has been shown to be safe and efficacious in newborns, is not burdened by these issues and should soon be available in all tertiary intensive care nurseries. Ideally, EST for the newborn with CDH will require prenatal diagnosis and in utero maternal transport to a tertiary perinatal/ neonatal center (surfactant replacement), but even in those instances when this anomaly goes undetected until birth and infant transport is required, EST may improve survival (surfactant rescue). EST should not preclude other forms of treatment for newborns with CDH, but instead could be used adjuvantly. These results suggest that EST for the high-risk neonate with CDH warrants further consideration and a randomized clinical trial is being planned.
ADDENDUM As of April 1992, we have now treated seven CDH newborns prophylactically with EST using the same criteria described herein. Excluding the one described, no further episodes of life-threatening pulmonary hypertension have occurred. Six of the patients have survived. The seventh patient had treatment withdrawn due to other lethal congenital anomalies (trisomy 18).
REFERENCES 1. Adzick NS, Harrison MR, Glick PL, et al: Diaphragmatic hernia in the fetus: Prenatal diagnosis and outcome in 94 cases. J Pediatr Surg 20:357-361,198s 2. Nakayama DK, Harrison MR, Chinn DH, et al: Prenatal
diagnosis and natural history of the fetus with a congenital diaphragmatic hernia: Initial clinical experience. J Pediatr Surg 20:118-124,1985 3. Beracerraf BR, Adzick NS: Fetal diaphragmatic hernia:
EXOGENOUS
SURFACTANT
THERAPY FOR CDH
Ultrasound diagnosis and clinical outcome in 19 cases. Am J Obstet 156:573-576,1987 4. Adzick NS, Vacanti JP, Lillehei CW: Fetal diaphragmatic hernia: Ultrasound diagnosis and clinical outcome in 38 cases. J Pediatr Surg 24:654-658,1989 5. Harrison MR, Bjordal RI, Langmark F, et al: Congenital diaphragmatic hernia: The hidden mortality. J Pediatr Surg 13:227230,1978 6. Adzick NS, Harrison MR, Outwater KM, et al: Correction of congenital diaphragmatic hernia in utero IV. An early gestational fetal lamb model for pulmonary vascular morphometric analysis. J Pediatr Surg 20:673-680,1985 7. Nguyen L, Guttman FM, De Chadarevian JP: The mortality of congenital diaphragmatic hernia. Is total pulmonary mass inadequate, no matter what? Ann Surg 198:766-770,1983 8. Reale FR, Esterly JR: Pulmonary hypoplasia: A morphometric study of the lungs of infants with diaphragmatic hernia, anencephaly, and renal malformations. Pediatrics 51:91-96,1973 9. Levin DL: Morphologic analysis of the pulmonary vascular bed in congenital left-sided diaphragmatic hernia. J Pediatr 92:805809,1978 10. Hislop A, Reid L: Persistent hypoplasia of the lung after repair of congenital diaphragmatic hernia. Thorax 31:450-455, 1976 11. Harrison MR, Jester JA, Ross NA: Correction of congenital diaphragmatic hernia in utero: I. The model: Intrathoracic balloon produces fatal pulmonary hypoplasia. Surgery 88:174-181,198O 12. Wigglesworth JS, Desai R, Guerrini P: Fetal lung hypoplasia: Biochemical and structural variations and their possible significance. Arch Dis Child 56:606-615, 1981 13. Sakai H, Tamura M, Hosokawa Y: Effect of surgical repair on respiratory mechanics in congenital diaphragmatic hernia. J Pediatr 111:432-438,1987 14. Hirthler MA, Bradley CA, Willis D, et al: The measurement of amniotic fluid phospholipids in congenital diaphragmatic hernia. Pediatr Surg Int (in press) 15. Bell M, Ternberg J: Antenatal diagnosis of diaphragmatic hernia. Pediatrics 60:738-740, 1977 16. Berk C, Grundy M: High risk lecithin/sphingomyelin ratios associated with neonatal diaphragmatic hernia. Case reports. Br J Obstet Gynaecol89:250-251, 1982 17. Hisanaga S, Shimokawa H, Kashiwabara Y: Unexpected low lecithin/sphingomyelin ratios associated with fetal diaphragmatic hernia. Am J Obstet Gynecol149:905-906,1984 18. Kwong MS, Egan EA, Notter RH, et al: Double-blinded clinical trial of calf lung surfactant extract for the prevention of hyaline membrane disease in extremely premature infants. Pediatrics 76585.592, 1985
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19. Goodfellow T, Hyde I, Burge DM: Congenital diaphragmatic hernia: The prognostic significance of the site of the stomach. Br J Radio1 60:993-995, 1987 20. Burge DM, Atwell JD, Freeman NV: Could the stomach site help predict outcome in babies with left-sided congenital diaphragmatic hernia diagnosed antenatally? J Pediatr Surg 24567-569. 1989 21. Bohn D, Tamura M, Perrin D, et al: Ventilator predictors of pulmonary hypoplasia in congenital diaphragmatic hernia, confirmed by morphologic assessment. J Pediatr 111:423-431, 1987 22. Avery ME. Mead J: Surface properties in relation to atelectasis and hyaline membrane disease. Am J Dis Child 97:517523,1959 23. Merritt TA, Hallman M: Surfactant replacement. Am J Dis Child 142:1333-1339.1988 24. Auten RL, Notter RH, Kendig JW, et al: Surfactant treatment of full term newborns with respiratory distress. Pediatrics 87:101-107, 1991 25. Pringle KC, Turner JW, Schofield JC, et al: Creation and repair of diaphragmatic hernia: Lung development and morphology. J Pediatr Surg 19:131-140,1984 26. Hashimoto EG, Pringle KC, Soper RT, et al: Creation and repair of diaphragmatic hernia: Morphology of the type II alveolar cell. J Pediatr Surg 20:354-356,1985 27. Glick PL, Stannard V, Leach CL, et al: Pathophysiology of congenital diaphragmatic hernia II: The fetal iamb CDH model is surfactant deficient. J Pediatr Surg 27:382-388, 1992 28. Harrison MR, Bressack MA, Churg AM, et al: Correction of congenital diaphragmatic hernia in utero II. Simulated correction permits lung growth with survival at birth. Surgery 88:260-268,198O 29. Harrison MR, Ross NA, de Lorimier AA: Correction of congenital diaphragmatic hernia in utero III. Development of a successful surgical technique using abdominoplasty to avoid compromise of umbilical blood flow. J Pediatr Surg 16:934-941,198l 30. Harrison MR: Congenital diaphragmatic hernia, in Harrison MR, Golbus MS, Filly RA (eds): The Unborn Patient-Prenatal Diagnosis and Treatment. Philadelphia, PA, Grune & Stratton, 1991, pp 295-333 31. Evans MI, Drugan A, Manning FA, et al: Fetal surgery in the 1990s. Am J Dis Child 143:1431-1436. 1989 32. Harrison MR, Langer JC, Adzick NS, et al: Correction of congenital diaphragmatic hernia in utero V: Initial clinical experience. J Pediatr Surg 25:47-57,199O 33. Harrison MR, Adzick NS, Longaker MT, et al: Successful repair in utero of a fetal diaphragmatic hernia after removal of the herniated viscera from the left thorax. N Engl J Med 322:15821584,199O
of Congenital Diaphragmatic Hernia III: Therapy for the High-Risk Neonate With CDH
By Philip L. Glick, Corinne L. Leach, Gail E. Besner, Edmund A. Egan, Frederick C. Morin, Anna Malanowska-Kantoch,
Luther K. Robinson, Alan Brody, Amol S. Lele, Margaret McDonnell, Bruce Holm,
Brian T. Rodgers, Michael E. Msall, Norman G. Courey, Melvin P. Karp, James E. Allen, Theodore C. Jewett, Jr, and Donald R. Cooney Buffalo, l Exogenous surfactant therapy (EST) in surfactantdeficient premature infants has been shown to improve lung compliance, decrease morbidity, and improve survival. Reports have demonstrated that newborns with congenital diaphragmatic hernia (CDH) have lung compliance, pressurevolume curves, and hyaline membrane formation resembling those changes seen in surfactant deficient premature newborns. We hypothesize that EST may also benefit infants with CDH. All high risk cases of prenatally diagnosed CDH at Children’s Hospital of Buffalo from November 1988 to February 1991 were prospectively evaluated for EST. In those families who chose to participate, the surfactant preparation, lnfasurf (100 mg/kg), was instilled into the newborn’s lungs prior to the first breath. The remainder of the perinatal, neonatal, and surgical care was performed in a routine manner. Three high-risk prenatally diagnosed newborns with left CDH were treated with EST. All showed signs of decreased pulmonary compliance. but could still be adequately oxygenated and ventilated. Surgical correction was performed after stabilization and all required patch closures. Two of the three infants suffered no life-threatening episodes of pulmonary hypertension and all survived. These infants had many known indicators for poor outcome in CDH with an expected survival of less than 20%. We believe that EST in these neonates with CDH contributed to their survival with minimum morbidity. These results suggest that surfactant replacement for the high-risk neonate with CDH warrants further consideration and a randomized clinical trial is being planned. Copyright Q 1992 by W.B. Saunders Company
INDEX WORDS: Congenital diaphragmatic replacement, therapy.
surfactant
therapy,
prenatal
hernia, surfactant diagnosis, fetal
From The Buffalo Institute of Fetal Therapy, the Children’s Hospital of Buffalo Perinatal Center, and the Departments of Surgery, Pediatrics, Radiology, and Obstetrics/Gynecology, School of Medicine and Biomedical Sciences, The University at Buffalo, State Universiv of New York, The Children’s Hospital of Buffalo, Buffalo, NY: Suppotted in part by The Women’s and Children’s Health Research Foundation of the Children’s Hospital of Buffalo, and BSRGIRDF Award, State University of New York at Buffalo. Presented at the 38th Annual International Congress of the British Association of Paediatn’c Surgeons, Budapest, Hungary, July 24-26, 1991. Address reprint requests to Philip L. Glick, MD, The Buffalo Institute of Fetal Therapy, The Children’s Hospital of Buffalo, 219 Byant St, Buffalo, NY 14222. Copyright o 1992 by WB. Saunders Company 0022-3468/92/2707-0020$03.~fO
066
New York
T
HE MORTALITY for congenital diaphragmatic hernia (CDH) remains between 50% and 88%.1-5 The high mortality in these infants has been attributed to the combination of pulmonary hypoplasia and pulmonary hypertension (pH).l~~-lOIn addition, studies in animal models and clinical reports have demonstrated that newborns with CDH have lung compliance, pressure-volume curves, and hyaline membrane formation resembling those changes seen in surfactant-deficient premature newborns.“-l3 Again, similar to premature newborns, amniotic fluid (AF) analysis has shown that full-term fetuses with prenatally diagnosed CDH have immature AF lecithinsphingomyelin (L/S) ratios and absent AF phosphatidylglycerol (PG). 14-17Exogenous surfactant therapy (EST) in premature infants with immature L/S ratios and absent PG has been shown to improve lung compliance, decrease morbidity, and improve survival.18 If the in utero mechanical effects of the herniated viscera in the chest of the fetus with CDH, which cause the pulmonary hypoplasia and PH, also result in a quantitative or functional surfactant deficiency, then it is possible to hypothesize that EST might also benefit infants with CDH. With this rationale in mind, we have recently cared for three newborns with prenatally diagnosed CDH, and treated them with EST. MATERIALS AND METHODS All high-risk cases (n = 3) of prenatally diagnosed CDH at Children’s Hospital of Buffalo from November 1988 to February 1991 were evaluated by our fetal therapy team (BIFT) and all the therapeutic options, ie, fetal surgery, maternal transport to a neonatal extracorporeal membrane oxygenation (ECMO) center, high-frequency ventilation, EST, or routine management, were considered. High risk was defined as those CDH diagnosed prenatally with associated polyhydramnios, dilated stomach in the chest, and the heart and mediastinum shifted to the contralateral chest wall.‘~4~19~u’ In the families who chose EST and after informed consent was given, Infasurf (100 mgikg; Ony Inc, Amherst, NY) was instilled into the newborn’s lungs via the endotracheal tube (ET) prior to the first breath. Infasurf is a calf lung surfactant extract used routinely in our intensive care nursery for the prevention/treatment of hyaline membrane disease in premature infants. The remainder of the perinatal, neonatal, and surgical care was performed in a routine manner.
JournalofPediatricSurgery,
Vol27, No 7 (July), 1992: pp
886-869
EXOGENOUS
SURFACTANT
867
THERAPY FOR CDH
Case Reports Case 1. A 35year-old woman (Gl, PO) was noted to have a size versus dates discrepancy in her fundal height at 35 weeks’ gestation. A level II obstetrical ultrasound examination showed the fetus to have a left CDH associated with polyhydramnios, dilated stomach in the chest, and the heart and mediastinum shifted to the right lateral chest wall. Amniocentesis for karyotype analysis showed 46,Xx. The family was referred to BIFT, the parents were counseled, and the options for care were outlined. The theoretical feasibility of surfactant replacement for this high-risk newborn was explained to the parents and they requested that we proceed. A 3.2-kg female was delivered at term, via a vaginal delivery. Infasurf was instilled via the ET into the lungs prior to the first breath. Hand ventilation with peak inspiratoty pressures (PIP) of 50 cm HzO, positive end-expiratory pressures (PEEP) of 4 cm HzO, and a rate of 60 breaths/min was required to generate a tidal volume sufficient to move the chest wall adequately. A nasogastric tube was placed. The infant was paralyzed (pancuronium, 0.1 mglkgih, intravenously [IV], as needed), sedated (fentanyl, 10 kg/kg/h, IV), and alkalinized (sodium bicarbonate, 1 mEq/kg/h, IV, and hyperventilation) to keep pH > 7.5 and PC02 25 to 30 mm Hg. The best preoperative, postductal arterial blood gas (ABG) (FIOz = lOO%, PIP = 40, PEEP = 2, mean airway pressure [MAP] = 17, rate = 60, and ventilatory index [VI] = 1,020) was 7.44/28/144/-4 (pHIPCOs/POJbase excess). A chest tube was inserted to treat a right pneumothorax. The infant was taken to the operating room at 3 hours of life and via a left subcostal approach, the stomach, the spleen, the entire small bowel, and a majority of the colon were found to have herniated through a 6 x 2 cm defect in the left diaphragm. A small airless left lung was noted. The hernia required a polytetrafluoroethylene (PTFE) patch to facilitate closure. A left chest tube was placed to 5 cm Hz0 water seal. In the first 24 hours postoperatively, representative simultaneous preductal and postductal ABGs (FIOz = 72%, PIP = 24, PEEP = 2, MAP = 10, rate = 45, VI = 450) were 7.51/24/278/-2 and 7.51/26/177/-2, respectively. On day of life 3, the paralysis was discontinued. Subsequently, the pH was allowed to normalize. The infant was weaned from the ventilator as tolerated and extubated on day 18. During this period the infant suffered no life-threatening episodes of PH. She was discharged home on day 41. The child shows no signs of chronic pulmonary disease. Neurodevelopmental follow-up at 35 months of age is normal. Case 2. A 35-year-old woman (Gl, PO) underwent routine ultrasound and amniocentesis (46,Xx) at 17 weeks’ gestation; ultrasound suggested a left CDH. At 29 weeks’ gestation the patient was referred to BIFI and the diagnosis of a left CDH with polyhydramnios, dilated stomach in the chest, with the heart and mediastinum shifted to the right was confirmed. The therapeutic options were explained and the family requested EST. At 31 weeks’ gestation, premature rupture of membranes (PROM) occurred. The mother was given betamethasone (9 mg/d, intramuscularly [IM]) and cesarean section was performed 48 hours later. A 2.09-kg female was delivered. Infasurf was instilled via the ET. The infant was paralyzed, sedated, alkalinized, and ventilated as described previously. Preoperatively, representative preductal and postductal ABGs (FI02 = lOO%, PIP = 25, PEEP = 3, rate = 82, VI = 820) were 7.51/29/493/ + 1 and 7.461311 67/+3 and measured compliance by an on-line pulmonary function computer (Pulmonary Evaluation and Diagnostic System [PEDS]; MAS Inc, Philadelphia, PA) was 0.23 mL/cm HzOlkg (normal, > 2.0 mL/cm HzOlkg). At 5 hours of age, the patient underwent an uneventful PTFE patch closure of the CDH and Ladd’s procedure.
For the first 96 hours postoperatively, the patient had persistent, but not life-threatening, PH with representative preductal and postductal ABGs (FIOr = 90%, PIP = 19, PEEP = 2. rate = 90) of 7.55/37/260/+9 and 7.55/34/107/+10. The paralysis was discontinued on day 2. The ventilator was gradually weaned, but on day 17 a repeat cardiac echo was performed because of failure to progress toward extubation. This showed a patent ductus arteriosus (PDA) with bidirectional shunting. On day 21 a PDA ligation was performed and the child was successfully extubated on day 31. The child underwent a Nissen fundoplication on day 42. The patient was discharged to home on day 63. This child shows no signs of chronic pulmonary disease and neurodevelopmental follow-up at 22 months is normal. Case 3. A 33-year-old woman (Gl, PO) underwent ultrasound at 28 weeks’ gestation showing a twin pregnancy. Twin A (46,XY) was normal, and twin B (46,Xx) was found to have a left CDH with polyhydramnios, dilated stomach in the chest, with the heart and mediastinum shifted to the right. The patient was referred to BIFT, and the therapeutic options were discussed with the family. EST for twin B in the delivery room was planned. PROM of twin A occurred at 33 weeks’ gestation. Amniocentesis results showed twin B to have an immature L/S ratio (1.2) and a negative PG. There was insufficient AF surrounding twin A to sample. The mother was treated with betamethasone (12 mg, IM) and underwent emergency cesarean section 8 hours later when the leg of twin A prolapsed. Twin A weighed 2.1 kg and had an uneventful delivery. Twin B weighed 1.7 kg and Infasurf was instilledvia the ET. The infant received cardiopulmonary resuscitation for several minutes in the delivery room because of persistent bradycardia. The baby was paralyzed, sedated, alkalinized, and ventilated as previously described. Preoperative representative preductal and postductal ABGs (FlOr = lOO%, PIP = 23. PEEP = 3, rate = 90, VI = 1,170) were 7.4013311551-3 and 7.341 40/95/ -4 and measured compliance by the PEDS was 0.22 mL/cm HzO/kg. At 3 hours of age the baby underwent an uneventful PTFE patch closure of the CDH. The patient did well for the first 15 hours postoperatively. Subsequently, she developed life-threatening PH with representative preductal and postductal ABGs (FIO;! = lOO%, PIP = 24, PEEP = 3, rate = 90) of 7.56/26/3561+3 and 7.36/54/35/+4. Cardiac echo showed decreased cardiac contractility with significant right-to-left shunt through a PDA. Prematurity and small size precluded consideration of ECMO. Severe PH persisted for the next 8 hours and then resolved. On day 3 alkalinization and paralysis were stopped. Ventilatory support was gradually weaned. On day 29 she was returned to the operating room for lysis of adhesions and a Ladd’s procedure. Extubation was accomplished on day 40. On day 70 she underwent a Nissen fundoplication. On day 97 she was discharged to home on bronchodilators and l/8 Llmin of 02, which were both subsequently stopped. Neurodevelopmental follow-up at 12 months is significant for a partial hearing loss as demonstrated by brain stem auditory evoked responses. The patient is being followed closely by our developmental and rehabilitation center. DISCUSSION These infants had many known high-risk factors for a poor prognosis in CDH, eg, prenatal diagnosis, polyhydramnios, dilated stomach in the chest, mediastinal shift, contralateral pneumothorax, VI > 1,000, and patch closure of the defect, with an expected survival of less than 20%.134J9-21EST may have re-
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duced surface tension and stabilized functional residual capacity in the hypoplastic lungs resulting in improved lung compliance, decreased barotrauma, enhanced pulmonary blood flow and gas exchange; may have prevented or limited barotrauma, which can cause life-threatening episodes of PH; and may have contributed to their survival with minimal morbidity. Respiratory distress syndrome (RDS) is caused by a surfactant deficiency, due to a decrease in surfactant synthesis or release by the alveolar type II pneumocyte.22,23 Kwong et al have shown in doubleblind, clinical human trials that EST prevents RDS in premature newborns and allows inspired oxygen, MAP, ventilator rate, and VI to be lower in the treated group during the first 48 hours of life when compared with untreated controls.18 In addition, there was an improved survival and lower morbidity in the surfactant-treated group. Most recently, Auten et al reported the efficacy of EST in 14 full-term neonates with respiratory failure.24 When compared with pretreatment parameters, all of their patients showed improvement in arterial-alveolar oxygenation ratio, oxygenation index, and chest radiographs. All patients survived and none required chronic oxygenation therapy. A surfactant deficiency contributing to the pathophysiology of CDH has been considered. Wigglesworth et al have reported that by histological, morphological, and quantitative biochemical criteria, the fetus/newborn with CDH shows many similarities to the premature, surfactant-deficient newborn with RDS.12 Pringle et al, using a fetal CDH lamb model, studied pulmonary maturity and morphology at various stages of gestation with electronmicroscopy.2,26 They showed that there was an increase in number and size of the type II pneumocyte, that these changes affected the ipsilateral greater than the contralateral lung, and that these changes were partially reversed by in utero CDH repair. No type II pneumocyte functional studies or surfactant analyses were performed. Full-term fetuses with prenatally diagnosed CDH have been found to have immature AF L/S ratios and absent AF PG, findings similar to premature surfactant-deficient newborns.14-I7 The present case 3 (twin B) had documented surfactantdeficient lungs (PG negative, L/S = 1.3), but because of twin A’s PROM, it is not clear whether the CDH and/or prematurity were the contributing factors. Additionally, data from our laboratory have con-
firmed a surfactant deficiency in the fetal lamb CDH mode1.27 In the unventilated CDH newborns at term, total lung lavage phospholipids were significantly different in quantity as well as composition when compared to controls. Type II pneumocyte synthesis of phosphatidylcholine was also decreased when compared with controls. These studies documenting a surfactant deficiency in the fetal lamb CDH model suggest that a similar pathophysiology may also be occurring in humans with CDH. Harrison’s pioneering work in fetal animal CDH preparations and human fetuses has been the benchmark of excellence and has provided the rationale for in utero correction of CDH.11,28-33The concept of EST in the high-risk newborn with CDH builds on many of these past accomplishments, but takes a different, perhaps more practical approach to the high-risk fetus/newborn with CDH. Even if Harrison’s proposed prospective human clinical trials demonstrate the efficacy of in utero CDH repair, the vast majority of the hundreds of newborns affected per year with CDH will not be able to take advantage of this treatment modality for obvious practical and ethical reasons.33 EST, which has been shown to be safe and efficacious in newborns, is not burdened by these issues and should soon be available in all tertiary intensive care nurseries. Ideally, EST for the newborn with CDH will require prenatal diagnosis and in utero maternal transport to a tertiary perinatal/ neonatal center (surfactant replacement), but even in those instances when this anomaly goes undetected until birth and infant transport is required, EST may improve survival (surfactant rescue). EST should not preclude other forms of treatment for newborns with CDH, but instead could be used adjuvantly. These results suggest that EST for the high-risk neonate with CDH warrants further consideration and a randomized clinical trial is being planned.
ADDENDUM As of April 1992, we have now treated seven CDH newborns prophylactically with EST using the same criteria described herein. Excluding the one described, no further episodes of life-threatening pulmonary hypertension have occurred. Six of the patients have survived. The seventh patient had treatment withdrawn due to other lethal congenital anomalies (trisomy 18).
REFERENCES 1. Adzick NS, Harrison MR, Glick PL, et al: Diaphragmatic hernia in the fetus: Prenatal diagnosis and outcome in 94 cases. J Pediatr Surg 20:357-361,198s 2. Nakayama DK, Harrison MR, Chinn DH, et al: Prenatal
diagnosis and natural history of the fetus with a congenital diaphragmatic hernia: Initial clinical experience. J Pediatr Surg 20:118-124,1985 3. Beracerraf BR, Adzick NS: Fetal diaphragmatic hernia:
EXOGENOUS
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Ultrasound diagnosis and clinical outcome in 19 cases. Am J Obstet 156:573-576,1987 4. Adzick NS, Vacanti JP, Lillehei CW: Fetal diaphragmatic hernia: Ultrasound diagnosis and clinical outcome in 38 cases. J Pediatr Surg 24:654-658,1989 5. Harrison MR, Bjordal RI, Langmark F, et al: Congenital diaphragmatic hernia: The hidden mortality. J Pediatr Surg 13:227230,1978 6. Adzick NS, Harrison MR, Outwater KM, et al: Correction of congenital diaphragmatic hernia in utero IV. An early gestational fetal lamb model for pulmonary vascular morphometric analysis. J Pediatr Surg 20:673-680,1985 7. Nguyen L, Guttman FM, De Chadarevian JP: The mortality of congenital diaphragmatic hernia. Is total pulmonary mass inadequate, no matter what? Ann Surg 198:766-770,1983 8. Reale FR, Esterly JR: Pulmonary hypoplasia: A morphometric study of the lungs of infants with diaphragmatic hernia, anencephaly, and renal malformations. Pediatrics 51:91-96,1973 9. Levin DL: Morphologic analysis of the pulmonary vascular bed in congenital left-sided diaphragmatic hernia. J Pediatr 92:805809,1978 10. Hislop A, Reid L: Persistent hypoplasia of the lung after repair of congenital diaphragmatic hernia. Thorax 31:450-455, 1976 11. Harrison MR, Jester JA, Ross NA: Correction of congenital diaphragmatic hernia in utero: I. The model: Intrathoracic balloon produces fatal pulmonary hypoplasia. Surgery 88:174-181,198O 12. Wigglesworth JS, Desai R, Guerrini P: Fetal lung hypoplasia: Biochemical and structural variations and their possible significance. Arch Dis Child 56:606-615, 1981 13. Sakai H, Tamura M, Hosokawa Y: Effect of surgical repair on respiratory mechanics in congenital diaphragmatic hernia. J Pediatr 111:432-438,1987 14. Hirthler MA, Bradley CA, Willis D, et al: The measurement of amniotic fluid phospholipids in congenital diaphragmatic hernia. Pediatr Surg Int (in press) 15. Bell M, Ternberg J: Antenatal diagnosis of diaphragmatic hernia. Pediatrics 60:738-740, 1977 16. Berk C, Grundy M: High risk lecithin/sphingomyelin ratios associated with neonatal diaphragmatic hernia. Case reports. Br J Obstet Gynaecol89:250-251, 1982 17. Hisanaga S, Shimokawa H, Kashiwabara Y: Unexpected low lecithin/sphingomyelin ratios associated with fetal diaphragmatic hernia. Am J Obstet Gynecol149:905-906,1984 18. Kwong MS, Egan EA, Notter RH, et al: Double-blinded clinical trial of calf lung surfactant extract for the prevention of hyaline membrane disease in extremely premature infants. Pediatrics 76585.592, 1985
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19. Goodfellow T, Hyde I, Burge DM: Congenital diaphragmatic hernia: The prognostic significance of the site of the stomach. Br J Radio1 60:993-995, 1987 20. Burge DM, Atwell JD, Freeman NV: Could the stomach site help predict outcome in babies with left-sided congenital diaphragmatic hernia diagnosed antenatally? J Pediatr Surg 24567-569. 1989 21. Bohn D, Tamura M, Perrin D, et al: Ventilator predictors of pulmonary hypoplasia in congenital diaphragmatic hernia, confirmed by morphologic assessment. J Pediatr 111:423-431, 1987 22. Avery ME. Mead J: Surface properties in relation to atelectasis and hyaline membrane disease. Am J Dis Child 97:517523,1959 23. Merritt TA, Hallman M: Surfactant replacement. Am J Dis Child 142:1333-1339.1988 24. Auten RL, Notter RH, Kendig JW, et al: Surfactant treatment of full term newborns with respiratory distress. Pediatrics 87:101-107, 1991 25. Pringle KC, Turner JW, Schofield JC, et al: Creation and repair of diaphragmatic hernia: Lung development and morphology. J Pediatr Surg 19:131-140,1984 26. Hashimoto EG, Pringle KC, Soper RT, et al: Creation and repair of diaphragmatic hernia: Morphology of the type II alveolar cell. J Pediatr Surg 20:354-356,1985 27. Glick PL, Stannard V, Leach CL, et al: Pathophysiology of congenital diaphragmatic hernia II: The fetal iamb CDH model is surfactant deficient. J Pediatr Surg 27:382-388, 1992 28. Harrison MR, Bressack MA, Churg AM, et al: Correction of congenital diaphragmatic hernia in utero II. Simulated correction permits lung growth with survival at birth. Surgery 88:260-268,198O 29. Harrison MR, Ross NA, de Lorimier AA: Correction of congenital diaphragmatic hernia in utero III. Development of a successful surgical technique using abdominoplasty to avoid compromise of umbilical blood flow. J Pediatr Surg 16:934-941,198l 30. Harrison MR: Congenital diaphragmatic hernia, in Harrison MR, Golbus MS, Filly RA (eds): The Unborn Patient-Prenatal Diagnosis and Treatment. Philadelphia, PA, Grune & Stratton, 1991, pp 295-333 31. Evans MI, Drugan A, Manning FA, et al: Fetal surgery in the 1990s. Am J Dis Child 143:1431-1436. 1989 32. Harrison MR, Langer JC, Adzick NS, et al: Correction of congenital diaphragmatic hernia in utero V: Initial clinical experience. J Pediatr Surg 25:47-57,199O 33. Harrison MR, Adzick NS, Longaker MT, et al: Successful repair in utero of a fetal diaphragmatic hernia after removal of the herniated viscera from the left thorax. N Engl J Med 322:15821584,199O