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Neurodevelopmental outcome after congenital diaphragmatic hernia: Extracorporeal membrane oxygenation before and after surgery
Journal of Pediatric Surgery VOL 36, NO 4
APRIL 2001
Neurodevelopmental Outcome After Congenital Diaphragmatic Hernia: Extracorporeal Membrane Oxygenation Before and After Surgery By Abdur Rasheed, Shauna Tindall, Deanna L. Cueny, Michael D. Klein, and Virginia Delaney-Black Detroit, Michigan
Background/Purpose: Extracorporeal membrane oxygenation (ECMO) as a treatment of last resort for neonates with persistent pulmonary hypertension of the newborn (PPHN) caused by congenital diaphragmatic hernia (CDH) may be used for preoperative stabilization or postoperative rescue. The aim of this study was to examine the acute and longterm morbidity associated with pre- and postoperative ECMO. Methods: Neonates born with CDH and needing ECMO were classified into 2 groups. Group 1 consisted of neonates placed on ECMO after CDH surgery. Patients in group 2 underwent preoperative ECMO stabilization. Medical records after birth were evaluated. Growth, neuromotor and cognitive development, hearing, and behavior were evaluated. Student t test and 2 were used to determine statistical significance between groups. Results: Subjects in group 2 had significantly more days on ECMO and loop diuretics. Alkalosis was induced for a longer
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ONGENITAL DIAPHRAGMATIC HERNIA (CDH) is a relatively common disorder with a prevalence of 1 in 2,000 to 5,000 births,1 occurring in about 1,114 babies per year in the United States. Approximately 434 deaths were related to this malformation during 1994.2 CDH also is associated with significant morbidity including esophageal ectasia, gastroesophageal reflux, poor weight gain during the first year of life, recurrence of the diaphragmatic hernia, and poor cognitive outcome.3 In 1995, Metkus et al4 found the average cost for a neonate with CDH was $137,000 for the initial hospitalization. They estimated the annual cost of the primary hospitalization alone for neonates with CDH to be $230 million per year in the United States. Infants born with CDH are at high risk for the development of persistent pulmonary hypertension of the
Journal of Pediatric Surgery, Vol 36, No 4 (April), 2001: pp 539-544
duration in group 2. At follow-up 3 to 9 years later, no differences were found between the 2 groups in growth parameters, neuromotor outcome, or behavior. However, in group 1, 2 of 9 children had significant hearing impairment necessitating amplification compared with 6 of 6 subjects in group 2.
Conclusions: Neonates with CDH first stabilized on ECMO (group 2) had a higher incidence of hearing loss compared with those needing ECMO postrepair (group 1). The etiology of this finding is not clear. This may be secondary to the prolonged period of hyperventilation or general intensive care that is part of the protocol for neonates who are electively stabilized on ECMO preoperatively. J Pediatr Surg 36:539-544. Copyright © 2001 by W.B. Saunders Company. INDEX WORDS: Congenital diaphragmatic hernia, extracorporeal membrane oxygenation, neurocognitive outcome, hearing loss.
newborn (PPHN), which contributes significantly to overall mortality rate.5-8 Extracorporeal membrane oxygenation (ECMO) has been used as a treatment of last resort for infants who have severe PPHN.9 The survival rate for infants born with CDH has remained relatively From the Departments of Pediatrics, Child Psychiatry and Psychology, Rehabilitation Services, and Surgery; Children’s Hospital of Michigan, Wayne State University School of Medicine, Detroit, MI. Presented orally in part at the 15th Annual CNMC Symposium on ECMO, Keystone, Colorado, February 1999. Address reprint requests to Virginia Delaney-Black, MD, MPH, Division of Neonatology, Children’s Hospital of Michigan, 3901 Beaubien, Detroit, MI 48201. Copyright © 2001 by W.B. Saunders Company 0022-3468/01/3604-0001$35.00/0 doi:10.1053/jpsu.2001.22278
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unchanged at about 50% to 60%10,11 in spite of the availability of ECMO for CDH repair beginning in the 1980s. The high mortality rate has led to the speculation that emergent operation in neonates with PPHN may cause reduction in lung compliance and worsen the pulmonary hypertension. In an attempt to reduce pulmonary hypertension, neonates with CDH have been stabilized on ECMO with corrective surgery performed only when the PPHN has improved.10 Many investigators believe that such delayed repair has increased the survival rate of infants with CDH,12-16 although uniformity of opinion does not exist.17-19 A recent study from this institution11 compared the survival rate in 3 groups of patients with CDH. Group A infants born before ECMO was available, had emergent repair. Group B infants were treated by immediate repair and when necessary postoperative ECMO was used. In group C, babies underwent preoperative stabilization using ECMO as indicated. The investigators concluded that although ECMO improved survival rate in newborns with CDH who present in early respiratory distress, there was no difference in mortality rate between groups B and C. They speculated, however, that morbidity between these 2 groups might be different because delayed repair allowed for better preoperative resuscitation and fewer ECMO complications.11,19 The current study was performed to evaluate the acute and long-term morbidity associated with these 2 protocols. We hypothesized that babies with CDH requiring ECMO support would have reduced neurodevelopmental morbidity if stabilized preoperatively on ECMO compared with postoperative ECMO rescue. By looking at the neurodevelopmental outcome, one more criterion might be described to assist physicians in making decisions about the management of CDH. MATERIALS AND METHODS The study sample consisted of all full-term and near-term (⬎34 weeks) survivors of CDH treated by ECMO at Children’s Hospital of Michigan (CHM) during the period January 1984 to April 1994. Objective criteria for ECMO included a partial pressure of oxygen in arterial blood of approximately 50 mm Hg or less with or without acute deterioration such as falling blood pressure in spite of maximal support, which included hyperventilation, paralyses, and pressors. Exclusion criteria for ECMO were birth weight below 2 kg, other major medical problems contraindicating anticoagulation and severe developmental abnormalities making survival unlikely (such as absent kidneys, chromosomal malformations, pulmonary hypoplasia). Group 1 (n ⫽ 12) was comprised of infants that were admitted between January 1984 and September 1989. These children were treated by immediate CDH repair and use of postoperative ECMO. Group 2 (n ⫽ 9) consisted of infants admitted from October 1989 through April 1994 who underwent a period of preoperative stabilization on ECMO. The past history of both groups was extracted from the medical records. Hyperventilation was defined as the length of time that the PCO2 was less than 25 mm Hg.20,21
Duration of alkalosis included the time, rounded to half hour, during which the pH value was ⱖ7.50.22 Total number of doses and days of ototoxic drugs including aminoglycosides, vancomycin, and loop diuretics (furosemide) were recorded. Developmental testing was conducted by a single child psychologist. Children from 6 to 16 years were tested with the Wechsler Intelligence Scales for Children, Third Edition (WISC-III).23 For younger children, the Wechsler Preschool and Primary Scales of Intelligence-Revised (WPPSI-R)24 was used. The WISC-III and WPPSI-R are standardized measures with a mean of 100 and SD of 15. Motor testing was conducted by 1 of 2 physical therapists. Group 1 was administered the Bruininks-Oseretsky Test of Motor Proficiency.25 This test is standardized for children 4.5 to 14 years of age. Group 2 was given the Peabody Developmental Motor Scales and Activity Cards.26 Standardization of this measure is available from birth to 83 months. Behavioral ratings were obtained with the Conners’ Teacher Rating Scale.27 This is a 39-item rating instrument that is completed by the child’s teacher. Standard scores (mean, 50; SD, 10) are computed in the following domains: hyperactivity, conduct problem, emotional overindulgent, anxious-passive, asocial and daydream-attention problem. Each child who was not receiving audiologic service also underwent tympanometry and pure tone audiogram (GSV 38V3 Auto Tymp. Model 1738 Grason-Standler, Inc, Milford, NH). For children with known hearing deficits requiring amplification aids, the most recent audiologic report was obtained from their physician/audiologist. Hearing impairment was defined as a child with hearing loss that required amplification or a minimal response level greater than 30 db at any of the octave frequencies from 500 to 4000 hz.28 Anthropometric measurements including weight, height and head circumference were plotted on standard growth curves.29 The mother’s educational level status was measured using the Hollingshead Index of Social Status (1975).30
RESULTS
Results were analyzed by 2 for nominal data and t test for continuous measures. Two of 21 children (1 in each group) died after their discharge from the hospital. Two families refused follow-up (group 1), and 2 children (group 2) were lost to follow-up. Among the children alive at the time of follow-up, 9 patients in group 1 (82%) and 6 in group 2 (75%) returned for developmental assessment. At the time of testing, the mean age of patients in group 1 was 8.8 years (range, 7 to 9 years), and in Group 2, 5.2 years (range, 3 to 6 years). Initial Hospitalization Characteristics of the 4 patients who did not return for follow-up were compared with the 15 patients tested (Table 1). Only 1 difference was observed: children in the group lost to follow-up had more ventilatory days. This finding was attributed to 1 child in the lost-to-follow-up group who was ventilated for 122 days. Because this patient was an outlier (value ⬎3SD from mean), windsorizing was used, after which no difference was found in the duration of ventilation between the 2 groups. Characteristics for patients who returned for developmental assessment are shown in Table 2. Comparison of group 1 and 2 patients showed that group 2 subjects had significantly more ECMO days. Moreover, children in group 2 were
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Table 1. Characteristics of Patients Lost to Follow-Up Compared With Those Undergoing Follow-Up Lost to Follow-Up (n ⫽ 4)
Characteristics
Gestational age Males Birth weight percentile Apgar Score 1 min 5 min Pre-EMCO AADO2 Hyperventilation (h) Assisted ventilation (d) ECMO (d) Patch Hospitalization (d)
Underwent Follow-Up (n ⫽ 15)
40 (39-40) 3 (75%) 51 (6-90)
40 (38-42) 10 (67%) 56 (10-93)
6 8 645 (SD 54, 580-712) 29 (SD 37, 1.5-80) 59 (SD 15, 9-71) 7 (SD 3, 4-10) 2 (50%) 77 (SD 65, 34-172)
6 7 621 (SD 54, 580-649) 32 (SD 30, 0-102) 26 (SD 58, 75-122) 6 (SD 4, 2-15) 10 (67%) 48 (SD 29, 20-130)
Significance
Not significant Not significant Not significant Not significant Not significant Not significant Not significant P ⫽ .03* Not significant Not significant Not significant
NOTE. Mean, standard deviation, and range provided where appropriate. * On windsorizing (see text) no significant difference was observed.
hyperventilated for a longer duration than group 1, although the difference did not reach significance (26 hours in group 1 v 42 hours in group 2; P ⫽ .31). Children in group 2 had a significant longer duration of alkalosis. Group 2 children showed a trend to have more number of doses and significant more days on furosemide. Although there was no statistical difference in the number of doses of aminoglycosides and vancomycin given to the 2 groups, group 2 showed a trend of being on the above antibiotics for more days. All known blood levels were in the nontoxic range. Developmental Outcome Follow-up data for the 2 groups (Table 3) shows no significant difference in growth parameters. There was
no child with diagnosis of cerebral palsy; furthermore, gross motor and fine motor performance between the 2 groups showed no significant difference. Moreover, the motor age equivalent and the mother’s education level were not significantly different. All 6 of the children in group 2 had hearing impairment as compared with those in group 1 with 2 of 9 impaired (P ⫽ .007). No group differences were observed on the Conners’ Teachers’ Rating. Data on cognitive outcomes are presented in Table 4. Children in both groups showed a range of cognitive abilities, from the mentally impaired to high average range (with 1 group 1 subject in the superior range). Children in group 1 showed a wide range of performance on WISC-III. Five children had Verbal IQ to Performance IQ (VIQ-
Table 2. Comparison of Characteristics During Initial Hospitalization by Treatment Group Group 1 (n ⫽ 9)
Group 2 (n ⫽ 6)
40 (SD 1, 38-41) 6 (67%) 48 (6-90)
39 (SD 2, 38-42) 4 (67%) 68 (10-90)
Characteristics
Gestational age (wk) Males Birth weight percentile Apgar Score 1 min 5 min Pre-ECMO AADO2 Hyperventilation (h) Assisted ventilation (d) ECMO (d) Gor-Tex patch Hospitalization (d) Alkalosis (h) Loop diuretics Doses Days Antibiotics Doses Days
6 7 613 26 23 5 6 41 83
(SD 23, 580-649) (SD 25, 0-81) (SD 10, 9-41) (SD 3, 2-8) (67%) (SD 19, 20-72)
6 8 633 42 31 9 4 58 167
(SD 16, 604-647) (SD 35, 12-102) (SD 23, 14-71) (SD 4, 5-15) (67%) (SD 41, 21-130)
Significant
Not significant Not significant Not significant Not significant Not significant Not significant Not significant Not significant P ⫽ .03 Not significant Not significant P ⫽ .022
14 9
34 19
P ⫽ .06 P ⫽ .03
28 10
10 4
Not significant P ⫽ .06
NOTE. Mean, standard deviation, and range provided as appropriate.
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Table 3. Developmental Outcome at Follow-Up
Weight percentile Height percentile Head circumference percentile Gross motor standard score Fine motor standard score Hearing impairment (n)
Group 1 (n ⫽ 9)
Group 2 (n ⫽ 6)
Significance
48 (11-93) 48 (⬍5-75) 47 (5-90) 93 (SD 24, ⬍55-124) 86 (SD 23, ⬍55-118) 2 (22%)
578 (5-⬎95) 53 (5-90) 84 (45-⬎98) 92 (SD 25, 69-131) 86 (SD 18, 65-106) 6 (100%)
Not significant Not significant Not significant Not significant Not significant P ⫽ .007
NOTE. Means, standard deviation, and range provided where appropriate.
PIQ) discrepancies of 15 points or higher; 3 had discrepancies greater than 26 points. Because of the severity of their hearing impairment, subjects in group 2 could not be evaluated reliably on verbal measures of cognitive ability. PIQ of children in group 2 generally were within the average range. DISCUSSION
Our hypothesis that patients with preoperative stabilization on ECMO (group 2) would have a better neurocognitive development was not supported in this study. On the contrary, this group had a significantly higher frequency of hearing impairment, clearly affecting their performance on traditional measures of intelligence. All 6 group 2 patients who were stabilized on ECMO before repair wore hearing aids as compared with only 2 in group 1 infants (22%). Davenport et al31 speculated that delayed CDH repair may involve an increased incidence of cerebral damage and later handicap caused by a prolongation of intensive care and resuscitation. This may be the case in our study. Group 2 patients were hyperventilated for a longer duration, thus potentially decreasing cerebral blood flow.32 Durations of length of ECMO and induced alkalosis were significantly longer for children in group 2. Various studies have found an association between hearing deficits and severe respiratory failure, hyperventilation and CDH alone, or in combination with ECMO therapy. Among the ototoxic medications, furosemide was used more often in group 2, in number of days. Group 1 patients showed a trend for more days on ototoxic antibiotics. Because their blood levels were in nontoxic range, the significance of this observation on hearing is questionable. Multiple factors may, therefore, play a role in causing hearing deficits in patients in group 2.32-37 Davenport et al31 report one of the few studies dealing with the long-term neurodevelopmental outcome of neonates with CDH who were treated with delayed repair. In this English study, 23 survivors over the period 1983 through 1989, (range, 18 months to 94 months) were evaluated. Only 2 children had major developmental disabilities. The mean developmental quotient (DQ) for the group was 108, and none had moderate to severe developmental delay (DQ ⬍70). The investigators con-
cluded that in CDH, delayed surgery with preoperative stabilization was not associated with an impaired developmental outcome. However, this was an uncontrolled study in which the number of patients needing preoperative ECMO stabilization was not reported. No child at follow-up had significant hearing impairment; however, the method of audiology testing was not mentioned. Stolar et al38 found CDH, male gender, and low level of maternal education to be risk factors for poor cognitive outcome in newborns requiring ECMO. On the measure of cognitive ability in this study, both groups of subjects showed a range of abilities (Table 4). Children treated with ECMO emergently (group 2) had a higher incidence of sensineural hearing loss, which interfered with the reliable administration of standardized measures of verbal cognitive abilities. Children with moderate to severe hearing impairments typically show verbal intelligence quotients (VIQs) that are approximately 2 standard deviations below the mean, whereas their performance intelligence quotients (PIQs) fall within the average range.39 Such differences may affect school performance and require special education services for the hearing impaired. Discrepancies in VIQPIQ of 15 points or higher were common in group 1. Such discrepancies generally are accepted as indicative Table 4. Cognitive Outcome Data Group/Patients
Verbal IQ
Performance IQ
Full IQ
1a 1b 1c 1d 1e 1f 1g 1h 1l 2a 2b 2c 2d 2e 2f
105 85 95 72 64 110 95 135 84 * * * * * *
102 57 98 98 73 94 88 120 52 84 94 118 101 ‡ 73
104 69 97 83 66 102 92 101 86 † † † † † †
* Net administered because of hearing impairment. † Not computed because full battery was not administered. ‡ Refused to cooperate. Two subtests were within average range.
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of cognitive processing problems, which may reflect a learning disability.40 Using these guidelines, 56% of subjects in group 1 would be suspect for such difficulties. Diagnosis of cerebral palsy typically is made after age 1 to 2 years because by 2 to 3 years of age the neuromotor status becomes stable.41 Therefore, cerebral palsy could be compared between the 2 groups. No difference in neuromotor development was found between groups. The 2 groups in the current study were part of larger groups of patients with CDH in the study by Lessin et al11 looking at babies who had an emergent operation versus those who were stabilized first, and placed on ECMO if needed. As a pilot project, we chose to include those patients who had severe PPHN requiring ECMO support, that is, the sickest neonates. We realize that the small sample size may affect outcome. Further study with a larger sample size will be needed to confirm these findings. Neonates with diaphragmatic hernia who undergo pre-
operative stabilization with ECMO may be at risk of increased morbidity because of an elective period of prolonged resuscitation. In our study, this is manifested by a significantly longer duration on ECMO, alkalosis, and loop diuretics. Although not significantly different, group 2 also required almost twice as many hours of hyperventilation as group 1 and twice as many doses of loop diuretics. Subsequent development of sensineural hearing loss was significantly greater in group 2. Cognitive data indicate that both groups of children are at risk for learning difficulties. However, children in group 2, because of their hearing impairment, appear to be at a greater risk for poor school outcome. Neonates with CDH on ECMO, especially those stabilized preoperatively should be monitored closely for hypocarbia and alkalosis. Loop diuretics should be used judiciously, and blood levels of ototoxic antibiotics should be closely followed. After discharge, regular prospective hearing evaluation is essential.
REFERENCES 1. Wienstein S, Stolar CJH: Newborn surgical emergencies, congenital diaphragmatic hernia and extracorporeal membrane oxygenation. Pediatr Clin North Amer 40:1315-1333, 1993 2. Langham MR, Kays DW, Ledbetter DJ, et al: Congenital diaphragmatic hernia, epidemiology and outcome. Clin Perinatol 23:671688, 1996 3. Van Meurs KP, Robbins ST, Karr SS, et al: Congenital diaphragmatic hernia: Long-term outcome in neonates treated with extracorporeal membrane oxygenation. J Pediatr Surg 122:893-899, 1993 4. Metkus AP, Esserman L, Sola A, et al: Cost per anomaly: What does a diaphragmatic hernia cost? J Pediatr Surg 30:226-230, 1995 5. Wohl MEB, Griscom NT, Strieder DJ, et al: The lung following repair of congenital diaphragmatic hernia. J Pediatr 90:405-413, 1977 6. Johnston PW, Liberman R, Gangitano E, et al: Ventilation parameters and arterial blood gases as a prediction of hypoplasia in congenital diaphragmatic hernia. J Pediatr Surg 26:248-254, 1991 7. Molenaar JC, Bos AP, Hazebroek WJ, et al: Congenital diaphragmatic hernia, what defect? J Pediatr Surg 26:248-254, 1991 8. Berdon WE, Baker DH, Amoury R: The role of pulmonary hypoplasia in the prognosis of newborn infants with diaphragmatic hernia and eventration. Am J Roentgenol 103:413-421, 1968 9. Shew SB, Davis B, Furck AK, et al: Congenital diaphragmatic hernia study group: Does extracorporeal membrane oxygenation improve survival in neonates with congenital diaphragmatic hernia? J Pediatr Surg 34:720-725, 1999 10. Clark RH, Harding WD, Hirschl RB, et al: Current surgical management of congenital diaphragmatic hernia: A report from the congenital diaphragmatic hernia study group. J Pediatr Surg 33:10041009, 1998 11. Lessin MS, Thompson IM, Deprez MF, et al: Congenital diaphragmatic hernia with or without extracorporeal membrane oxygenation: Are we making progress? J Am Coll Surg 181:65-71, 1995 12. Heiss K, Manning P, Oldham KT, et al: Reversal of mortality for congenital diaphragmatic hernia with ECMO. Ann Surg 209:225-230, 1989 13. West KW, Bengston K, Rescorla FJ, et al: Delayed surgical repair and ECMO improves survival in congenital diaphragmatic hernia. Ann Surg 216:454-462, 1989 14. Breaux CW, Rouse TM, Cain WS, et al: Improvement in
survival of patients with congenital diaphragmatic hernia utilizing a strategy of delayed repair after medical and/or extracorporeal membrane oxygenation stabilization. J Pediatr Surg 26:333-338, 1991 15. Nakayama DK, Motoyama EK, Tagge EM: Effect of preoperative stabilization on respiratory system compliance and outcome in newborn infants with congenital diaphragmatic hernia. J Pediatr 118: 793-799, 1981 16. Reickert CA, Hirschl RB, Schumacker R, et al: Effect of very delayed repair of congenital diaphragmatic hernia on survival and extracorporeal life support use. Surgery 120:766-773, 1996 17. Wilson JM, Lund DP, Lillehei CW, et al: Delayed repair and preoperative stabilization does not improve survival in high-risk congenital diaphragmatic hernia. J Pediatr Surg 27:368-375, 1992 18. Charlton AG, Bruce J, Davenport M: Timing of surgery in congenital diaphragmatic hernia. Low mortality after preoperative stabilization. Anesthesia 46:820-823, 1991 19. Coughlin JP, Drucker DE, Cullen ML, et al: Delayed repair of congenital diaphragmatic hernia. Am Surg 59:90-93, 1993 20. Wiswell TE, Graziani LJ, Kornhauser MS, et al: Effect of hypocarbia on the development of cystic periventricular leukomalacia in premature infants treated with high-frequency jet ventilation. Pediatrics 98:918-924, 1996 21. Ferrara B, Johnson DE, Chang P, et al: Efficacy and neurological outcome of profound hypocapneic alkalosis for the treatment of persistent pulmonary hypertension in infancy. J Pediatr 105:457-461, 1984 22. Walsh-Sukys MC: Persistent pulmonary hypertension of newborn, black box revisited. Clin Perinatol 20:127-143, 1993 23. Weschler D: Weschler Intelligence Scale for Children (ed 3). New York, NY, Harcourt Brace Jovanovich, 1991 24. Weschler D: Weschler Preschool and Primary of IntelligenceRevised. New York, NY, Harcourt Brace Jovanovich, 1989 25. Bruininks RH (ed): Bruininks-Oseretsky Test of Motor Proficiency Examiner’s Manual. Minnesota, American Guidance Service, 1978 26. Folio R, Fewell RR: Peabody Developmental Motor Scale. Needham F (ed). Allen, TX, DLM Teaching Resources, 1983, pp 1-65 27. Conners CK: Conners’ Rating Scales Manual. Conners CK (ed). North Townawanda, NY. Multi-Health Systems, 1989
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28. Hendricks-Munoz KD, Walton JP: Hearing loss in infants with persistent fetal circulation. Pediatrics 81:650-656, 1988 29. Hamill PVV, Drizd TA, Johnson CL, et al: Physical growth: National Center for Health Statistics percentiles. Am J Clin Nutr 32:607-629, 1979 30. Hollingshead AB (ed): Four-Factor Index of Social Status. New Haven, CT, Department of Sociology, Yale University, 1975 31. Davenport M, Rivlin E, D’Souza SW, et al: Delayed surgery for congenital diaphragmatic hernia: Neurodevelopmental outcome in later childhood. Arch Dis Child 67:1353-1356, 1992 32. Bifano EM, Pfannenstiel A: Duration of hyperventilation and outcome in infants with persistent pulmonary hypertension. Pediatrics 81:657-661, 1988 33. Sweitzer RS, Lowry JK, Georgeson KE, et al: Hearing loss associated with neonatal ECMO: A clinical investigation. Int J Pediatr Otorhinolarngol 41:339-345, 1997 34. Kawashiro N, Tsuchihashi N, Koga K, et al: Delayed postneonatal intensive care unit hearing disturbance. Int J Pediatr Otolaryngol 34:35-43, 1996 35. Cheung P, Haluschak MM, Finer NN, et al: Sensineural hearing
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loss in survivors of neonatal extracorporeal membrane oxygenation. Early Human Development 44:225-233, 1996 36. Robertson CMT, Cheung P, Meredith HM, et al: High prevalence of sensineural hearing loss among survivors of neonatal congenital diaphragmatic hernia. Am J Otol 19:730-736, 1998 37. Lasky RE, Wiorek L, Becker TR: Hearing loss in survivors of neonatal extracorporeal membrane oxygenation (ECMO) therapy and high frequency oscillatory (HFO) therapy. J Am Acad Audiol 9:47-58, 1998 38. Stolar CJH, Crisafi MA, Driscoll YT: Neurocognitive outcome for neonates treated with extracorporeal membrane oxygenation: Are infants with congenital diaphragmatic hernia different? J Pediatr Surg 30:366-372, 1995 39. Sullivan PM, Montoya LA: Factor analysis of the WISC-III with deaf and hard-of-hearing children. Psychological Assessment 9:317321, 1997 40. Kaufman AS: Seven Steps for Interpreting the WISC-III Profile: From IQ’s to Factors Indexes to Scaled Scores. Intelligent Testing With WISC-III. New York, NY, John Wiley & Sons, 1994, pp 97-143 41. Harris SR: Early diagnosis of spastic diplegia, spastic hemiplegia, and quadriplegia. Am J Dis Child 143:1356-1360, 1989
APRIL 2001
Neurodevelopmental Outcome After Congenital Diaphragmatic Hernia: Extracorporeal Membrane Oxygenation Before and After Surgery By Abdur Rasheed, Shauna Tindall, Deanna L. Cueny, Michael D. Klein, and Virginia Delaney-Black Detroit, Michigan
Background/Purpose: Extracorporeal membrane oxygenation (ECMO) as a treatment of last resort for neonates with persistent pulmonary hypertension of the newborn (PPHN) caused by congenital diaphragmatic hernia (CDH) may be used for preoperative stabilization or postoperative rescue. The aim of this study was to examine the acute and longterm morbidity associated with pre- and postoperative ECMO. Methods: Neonates born with CDH and needing ECMO were classified into 2 groups. Group 1 consisted of neonates placed on ECMO after CDH surgery. Patients in group 2 underwent preoperative ECMO stabilization. Medical records after birth were evaluated. Growth, neuromotor and cognitive development, hearing, and behavior were evaluated. Student t test and 2 were used to determine statistical significance between groups. Results: Subjects in group 2 had significantly more days on ECMO and loop diuretics. Alkalosis was induced for a longer
C
ONGENITAL DIAPHRAGMATIC HERNIA (CDH) is a relatively common disorder with a prevalence of 1 in 2,000 to 5,000 births,1 occurring in about 1,114 babies per year in the United States. Approximately 434 deaths were related to this malformation during 1994.2 CDH also is associated with significant morbidity including esophageal ectasia, gastroesophageal reflux, poor weight gain during the first year of life, recurrence of the diaphragmatic hernia, and poor cognitive outcome.3 In 1995, Metkus et al4 found the average cost for a neonate with CDH was $137,000 for the initial hospitalization. They estimated the annual cost of the primary hospitalization alone for neonates with CDH to be $230 million per year in the United States. Infants born with CDH are at high risk for the development of persistent pulmonary hypertension of the
Journal of Pediatric Surgery, Vol 36, No 4 (April), 2001: pp 539-544
duration in group 2. At follow-up 3 to 9 years later, no differences were found between the 2 groups in growth parameters, neuromotor outcome, or behavior. However, in group 1, 2 of 9 children had significant hearing impairment necessitating amplification compared with 6 of 6 subjects in group 2.
Conclusions: Neonates with CDH first stabilized on ECMO (group 2) had a higher incidence of hearing loss compared with those needing ECMO postrepair (group 1). The etiology of this finding is not clear. This may be secondary to the prolonged period of hyperventilation or general intensive care that is part of the protocol for neonates who are electively stabilized on ECMO preoperatively. J Pediatr Surg 36:539-544. Copyright © 2001 by W.B. Saunders Company. INDEX WORDS: Congenital diaphragmatic hernia, extracorporeal membrane oxygenation, neurocognitive outcome, hearing loss.
newborn (PPHN), which contributes significantly to overall mortality rate.5-8 Extracorporeal membrane oxygenation (ECMO) has been used as a treatment of last resort for infants who have severe PPHN.9 The survival rate for infants born with CDH has remained relatively From the Departments of Pediatrics, Child Psychiatry and Psychology, Rehabilitation Services, and Surgery; Children’s Hospital of Michigan, Wayne State University School of Medicine, Detroit, MI. Presented orally in part at the 15th Annual CNMC Symposium on ECMO, Keystone, Colorado, February 1999. Address reprint requests to Virginia Delaney-Black, MD, MPH, Division of Neonatology, Children’s Hospital of Michigan, 3901 Beaubien, Detroit, MI 48201. Copyright © 2001 by W.B. Saunders Company 0022-3468/01/3604-0001$35.00/0 doi:10.1053/jpsu.2001.22278
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unchanged at about 50% to 60%10,11 in spite of the availability of ECMO for CDH repair beginning in the 1980s. The high mortality rate has led to the speculation that emergent operation in neonates with PPHN may cause reduction in lung compliance and worsen the pulmonary hypertension. In an attempt to reduce pulmonary hypertension, neonates with CDH have been stabilized on ECMO with corrective surgery performed only when the PPHN has improved.10 Many investigators believe that such delayed repair has increased the survival rate of infants with CDH,12-16 although uniformity of opinion does not exist.17-19 A recent study from this institution11 compared the survival rate in 3 groups of patients with CDH. Group A infants born before ECMO was available, had emergent repair. Group B infants were treated by immediate repair and when necessary postoperative ECMO was used. In group C, babies underwent preoperative stabilization using ECMO as indicated. The investigators concluded that although ECMO improved survival rate in newborns with CDH who present in early respiratory distress, there was no difference in mortality rate between groups B and C. They speculated, however, that morbidity between these 2 groups might be different because delayed repair allowed for better preoperative resuscitation and fewer ECMO complications.11,19 The current study was performed to evaluate the acute and long-term morbidity associated with these 2 protocols. We hypothesized that babies with CDH requiring ECMO support would have reduced neurodevelopmental morbidity if stabilized preoperatively on ECMO compared with postoperative ECMO rescue. By looking at the neurodevelopmental outcome, one more criterion might be described to assist physicians in making decisions about the management of CDH. MATERIALS AND METHODS The study sample consisted of all full-term and near-term (⬎34 weeks) survivors of CDH treated by ECMO at Children’s Hospital of Michigan (CHM) during the period January 1984 to April 1994. Objective criteria for ECMO included a partial pressure of oxygen in arterial blood of approximately 50 mm Hg or less with or without acute deterioration such as falling blood pressure in spite of maximal support, which included hyperventilation, paralyses, and pressors. Exclusion criteria for ECMO were birth weight below 2 kg, other major medical problems contraindicating anticoagulation and severe developmental abnormalities making survival unlikely (such as absent kidneys, chromosomal malformations, pulmonary hypoplasia). Group 1 (n ⫽ 12) was comprised of infants that were admitted between January 1984 and September 1989. These children were treated by immediate CDH repair and use of postoperative ECMO. Group 2 (n ⫽ 9) consisted of infants admitted from October 1989 through April 1994 who underwent a period of preoperative stabilization on ECMO. The past history of both groups was extracted from the medical records. Hyperventilation was defined as the length of time that the PCO2 was less than 25 mm Hg.20,21
Duration of alkalosis included the time, rounded to half hour, during which the pH value was ⱖ7.50.22 Total number of doses and days of ototoxic drugs including aminoglycosides, vancomycin, and loop diuretics (furosemide) were recorded. Developmental testing was conducted by a single child psychologist. Children from 6 to 16 years were tested with the Wechsler Intelligence Scales for Children, Third Edition (WISC-III).23 For younger children, the Wechsler Preschool and Primary Scales of Intelligence-Revised (WPPSI-R)24 was used. The WISC-III and WPPSI-R are standardized measures with a mean of 100 and SD of 15. Motor testing was conducted by 1 of 2 physical therapists. Group 1 was administered the Bruininks-Oseretsky Test of Motor Proficiency.25 This test is standardized for children 4.5 to 14 years of age. Group 2 was given the Peabody Developmental Motor Scales and Activity Cards.26 Standardization of this measure is available from birth to 83 months. Behavioral ratings were obtained with the Conners’ Teacher Rating Scale.27 This is a 39-item rating instrument that is completed by the child’s teacher. Standard scores (mean, 50; SD, 10) are computed in the following domains: hyperactivity, conduct problem, emotional overindulgent, anxious-passive, asocial and daydream-attention problem. Each child who was not receiving audiologic service also underwent tympanometry and pure tone audiogram (GSV 38V3 Auto Tymp. Model 1738 Grason-Standler, Inc, Milford, NH). For children with known hearing deficits requiring amplification aids, the most recent audiologic report was obtained from their physician/audiologist. Hearing impairment was defined as a child with hearing loss that required amplification or a minimal response level greater than 30 db at any of the octave frequencies from 500 to 4000 hz.28 Anthropometric measurements including weight, height and head circumference were plotted on standard growth curves.29 The mother’s educational level status was measured using the Hollingshead Index of Social Status (1975).30
RESULTS
Results were analyzed by 2 for nominal data and t test for continuous measures. Two of 21 children (1 in each group) died after their discharge from the hospital. Two families refused follow-up (group 1), and 2 children (group 2) were lost to follow-up. Among the children alive at the time of follow-up, 9 patients in group 1 (82%) and 6 in group 2 (75%) returned for developmental assessment. At the time of testing, the mean age of patients in group 1 was 8.8 years (range, 7 to 9 years), and in Group 2, 5.2 years (range, 3 to 6 years). Initial Hospitalization Characteristics of the 4 patients who did not return for follow-up were compared with the 15 patients tested (Table 1). Only 1 difference was observed: children in the group lost to follow-up had more ventilatory days. This finding was attributed to 1 child in the lost-to-follow-up group who was ventilated for 122 days. Because this patient was an outlier (value ⬎3SD from mean), windsorizing was used, after which no difference was found in the duration of ventilation between the 2 groups. Characteristics for patients who returned for developmental assessment are shown in Table 2. Comparison of group 1 and 2 patients showed that group 2 subjects had significantly more ECMO days. Moreover, children in group 2 were
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Table 1. Characteristics of Patients Lost to Follow-Up Compared With Those Undergoing Follow-Up Lost to Follow-Up (n ⫽ 4)
Characteristics
Gestational age Males Birth weight percentile Apgar Score 1 min 5 min Pre-EMCO AADO2 Hyperventilation (h) Assisted ventilation (d) ECMO (d) Patch Hospitalization (d)
Underwent Follow-Up (n ⫽ 15)
40 (39-40) 3 (75%) 51 (6-90)
40 (38-42) 10 (67%) 56 (10-93)
6 8 645 (SD 54, 580-712) 29 (SD 37, 1.5-80) 59 (SD 15, 9-71) 7 (SD 3, 4-10) 2 (50%) 77 (SD 65, 34-172)
6 7 621 (SD 54, 580-649) 32 (SD 30, 0-102) 26 (SD 58, 75-122) 6 (SD 4, 2-15) 10 (67%) 48 (SD 29, 20-130)
Significance
Not significant Not significant Not significant Not significant Not significant Not significant Not significant P ⫽ .03* Not significant Not significant Not significant
NOTE. Mean, standard deviation, and range provided where appropriate. * On windsorizing (see text) no significant difference was observed.
hyperventilated for a longer duration than group 1, although the difference did not reach significance (26 hours in group 1 v 42 hours in group 2; P ⫽ .31). Children in group 2 had a significant longer duration of alkalosis. Group 2 children showed a trend to have more number of doses and significant more days on furosemide. Although there was no statistical difference in the number of doses of aminoglycosides and vancomycin given to the 2 groups, group 2 showed a trend of being on the above antibiotics for more days. All known blood levels were in the nontoxic range. Developmental Outcome Follow-up data for the 2 groups (Table 3) shows no significant difference in growth parameters. There was
no child with diagnosis of cerebral palsy; furthermore, gross motor and fine motor performance between the 2 groups showed no significant difference. Moreover, the motor age equivalent and the mother’s education level were not significantly different. All 6 of the children in group 2 had hearing impairment as compared with those in group 1 with 2 of 9 impaired (P ⫽ .007). No group differences were observed on the Conners’ Teachers’ Rating. Data on cognitive outcomes are presented in Table 4. Children in both groups showed a range of cognitive abilities, from the mentally impaired to high average range (with 1 group 1 subject in the superior range). Children in group 1 showed a wide range of performance on WISC-III. Five children had Verbal IQ to Performance IQ (VIQ-
Table 2. Comparison of Characteristics During Initial Hospitalization by Treatment Group Group 1 (n ⫽ 9)
Group 2 (n ⫽ 6)
40 (SD 1, 38-41) 6 (67%) 48 (6-90)
39 (SD 2, 38-42) 4 (67%) 68 (10-90)
Characteristics
Gestational age (wk) Males Birth weight percentile Apgar Score 1 min 5 min Pre-ECMO AADO2 Hyperventilation (h) Assisted ventilation (d) ECMO (d) Gor-Tex patch Hospitalization (d) Alkalosis (h) Loop diuretics Doses Days Antibiotics Doses Days
6 7 613 26 23 5 6 41 83
(SD 23, 580-649) (SD 25, 0-81) (SD 10, 9-41) (SD 3, 2-8) (67%) (SD 19, 20-72)
6 8 633 42 31 9 4 58 167
(SD 16, 604-647) (SD 35, 12-102) (SD 23, 14-71) (SD 4, 5-15) (67%) (SD 41, 21-130)
Significant
Not significant Not significant Not significant Not significant Not significant Not significant Not significant Not significant P ⫽ .03 Not significant Not significant P ⫽ .022
14 9
34 19
P ⫽ .06 P ⫽ .03
28 10
10 4
Not significant P ⫽ .06
NOTE. Mean, standard deviation, and range provided as appropriate.
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Table 3. Developmental Outcome at Follow-Up
Weight percentile Height percentile Head circumference percentile Gross motor standard score Fine motor standard score Hearing impairment (n)
Group 1 (n ⫽ 9)
Group 2 (n ⫽ 6)
Significance
48 (11-93) 48 (⬍5-75) 47 (5-90) 93 (SD 24, ⬍55-124) 86 (SD 23, ⬍55-118) 2 (22%)
578 (5-⬎95) 53 (5-90) 84 (45-⬎98) 92 (SD 25, 69-131) 86 (SD 18, 65-106) 6 (100%)
Not significant Not significant Not significant Not significant Not significant P ⫽ .007
NOTE. Means, standard deviation, and range provided where appropriate.
PIQ) discrepancies of 15 points or higher; 3 had discrepancies greater than 26 points. Because of the severity of their hearing impairment, subjects in group 2 could not be evaluated reliably on verbal measures of cognitive ability. PIQ of children in group 2 generally were within the average range. DISCUSSION
Our hypothesis that patients with preoperative stabilization on ECMO (group 2) would have a better neurocognitive development was not supported in this study. On the contrary, this group had a significantly higher frequency of hearing impairment, clearly affecting their performance on traditional measures of intelligence. All 6 group 2 patients who were stabilized on ECMO before repair wore hearing aids as compared with only 2 in group 1 infants (22%). Davenport et al31 speculated that delayed CDH repair may involve an increased incidence of cerebral damage and later handicap caused by a prolongation of intensive care and resuscitation. This may be the case in our study. Group 2 patients were hyperventilated for a longer duration, thus potentially decreasing cerebral blood flow.32 Durations of length of ECMO and induced alkalosis were significantly longer for children in group 2. Various studies have found an association between hearing deficits and severe respiratory failure, hyperventilation and CDH alone, or in combination with ECMO therapy. Among the ototoxic medications, furosemide was used more often in group 2, in number of days. Group 1 patients showed a trend for more days on ototoxic antibiotics. Because their blood levels were in nontoxic range, the significance of this observation on hearing is questionable. Multiple factors may, therefore, play a role in causing hearing deficits in patients in group 2.32-37 Davenport et al31 report one of the few studies dealing with the long-term neurodevelopmental outcome of neonates with CDH who were treated with delayed repair. In this English study, 23 survivors over the period 1983 through 1989, (range, 18 months to 94 months) were evaluated. Only 2 children had major developmental disabilities. The mean developmental quotient (DQ) for the group was 108, and none had moderate to severe developmental delay (DQ ⬍70). The investigators con-
cluded that in CDH, delayed surgery with preoperative stabilization was not associated with an impaired developmental outcome. However, this was an uncontrolled study in which the number of patients needing preoperative ECMO stabilization was not reported. No child at follow-up had significant hearing impairment; however, the method of audiology testing was not mentioned. Stolar et al38 found CDH, male gender, and low level of maternal education to be risk factors for poor cognitive outcome in newborns requiring ECMO. On the measure of cognitive ability in this study, both groups of subjects showed a range of abilities (Table 4). Children treated with ECMO emergently (group 2) had a higher incidence of sensineural hearing loss, which interfered with the reliable administration of standardized measures of verbal cognitive abilities. Children with moderate to severe hearing impairments typically show verbal intelligence quotients (VIQs) that are approximately 2 standard deviations below the mean, whereas their performance intelligence quotients (PIQs) fall within the average range.39 Such differences may affect school performance and require special education services for the hearing impaired. Discrepancies in VIQPIQ of 15 points or higher were common in group 1. Such discrepancies generally are accepted as indicative Table 4. Cognitive Outcome Data Group/Patients
Verbal IQ
Performance IQ
Full IQ
1a 1b 1c 1d 1e 1f 1g 1h 1l 2a 2b 2c 2d 2e 2f
105 85 95 72 64 110 95 135 84 * * * * * *
102 57 98 98 73 94 88 120 52 84 94 118 101 ‡ 73
104 69 97 83 66 102 92 101 86 † † † † † †
* Net administered because of hearing impairment. † Not computed because full battery was not administered. ‡ Refused to cooperate. Two subtests were within average range.
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of cognitive processing problems, which may reflect a learning disability.40 Using these guidelines, 56% of subjects in group 1 would be suspect for such difficulties. Diagnosis of cerebral palsy typically is made after age 1 to 2 years because by 2 to 3 years of age the neuromotor status becomes stable.41 Therefore, cerebral palsy could be compared between the 2 groups. No difference in neuromotor development was found between groups. The 2 groups in the current study were part of larger groups of patients with CDH in the study by Lessin et al11 looking at babies who had an emergent operation versus those who were stabilized first, and placed on ECMO if needed. As a pilot project, we chose to include those patients who had severe PPHN requiring ECMO support, that is, the sickest neonates. We realize that the small sample size may affect outcome. Further study with a larger sample size will be needed to confirm these findings. Neonates with diaphragmatic hernia who undergo pre-
operative stabilization with ECMO may be at risk of increased morbidity because of an elective period of prolonged resuscitation. In our study, this is manifested by a significantly longer duration on ECMO, alkalosis, and loop diuretics. Although not significantly different, group 2 also required almost twice as many hours of hyperventilation as group 1 and twice as many doses of loop diuretics. Subsequent development of sensineural hearing loss was significantly greater in group 2. Cognitive data indicate that both groups of children are at risk for learning difficulties. However, children in group 2, because of their hearing impairment, appear to be at a greater risk for poor school outcome. Neonates with CDH on ECMO, especially those stabilized preoperatively should be monitored closely for hypocarbia and alkalosis. Loop diuretics should be used judiciously, and blood levels of ototoxic antibiotics should be closely followed. After discharge, regular prospective hearing evaluation is essential.
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