Long-term follow up of infants with congenital diaphragmatic hernia

Seminars in Pediatric Surgery (2007) 16, 134-144

Long-term follow up of infants with congenital diaphragmatic hernia Pietro Bagolan, MD, Francesco Morini, MD From the Department of Medical and Surgical Neonatology, “Bambino Gesù” Children’s Hospital, Rome, Italy. KEYWORDS Congenital diaphragmatic hernia; Gastro-esophageal reflux; Musculoskeletal abnormalities; Neurodevelopmental outcome; Pulmonary morbidity; Quality of life

With improving treatment strategies for congenital diaphragmatic hernia (CDH) infants, an increase in survival of more severely affected patients can be expected. Consequently, more attention is now focused on long-term follow up of these patients. Many reports have emphasized associated morbidity, including pulmonary sequelae, neurodevelopmental deficits, gastrointestinal disorders, and other abnormalities. Therefore, survivors of CDH remain a complex patient population to care for throughout infancy and childhood, thus requiring long-term follow up. Much information has been provided from many centers regarding individual institutional improvements in overall survival. Few of these, however, have reported long-term follow up. The aim of this review is to describe the long-term outcome of survivors with CDH and to suggest a possible follow-up protocol for these patients. © 2007 Elsevier Inc. All rights reserved.

In 1946, Gross reported the first successful repair of a congenital diaphragmatic hernia (CDH) in a newborn less than 24 hours of age.1 At that time, CDH was considered a surgical emergency and immediate repair was the mainstay of the treatment with 90% to 95% reported survival rates.2 It later became apparent that this excellent survival was only the “visible” or operative survival rate of infants with CDH and that a hidden mortality existed due to death in utero or soon after birth, before the infant could be operated on, reducing the actual survival rate to below 50%.3,4 Beginning in the late 1970s, the introduction of new treatment modalities, including extracorporeal membrane oxygenation (ECMO), gentle ventilation with permissive hypercapnea, high frequency ventilation (HFV), and inhaled nitric oxide (iNO), resulted in an increase in overall survival of CDH patients.5-10 As a consequence of the increased survival of more severely affected infants, the long-term outcome of survivors with CDH became an important issue in the manAddress reprint requests and correspondence: Pietro Bagolan, MD, Department of Medical and Surgical Neonatology, “Bambino Gesù” Children’s Hospital, Piazza S. Onofrio, 4 00165 Rome, Italy. E-mail: [email protected].

1055-8586/$ -see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1053/j.sempedsurg.2007.01.009

agement of such patients, because CDH survivors can suffer long-term sequelae, including pulmonary and gastrointestinal problems, neurodevelopmental morbidity, and orthopedic disorders.11 Although some single-institution reports have addressed the issue of long-term outcome of CDH survivors, the variability in patient populations, management, and methods for and length of follow up make it difficult to draw firm conclusions about the quality of life of these patients. The aim of this review is to describe the long-term outcomes of survivors with CDH and to suggest a possible follow-up protocol for these patients.

Pulmonary outcome Most adolescent CDH survivors are healthy and enjoy normal lives. However, in a significant proportion of patients, long-term pulmonary sequelae are detectable and dependent on the severity of lung hypoplasia and the degree of lung injury.8,10-23 Before the introduction of “advanced” treatment modalities (ECMO, gentle ventilation, HFV, iNO), long-term

Bagolan and Morini

Long-Term Follow Up of CDH

CDH survivors treated with conventional mechanical ventilation were reported healthy and without clinically evident respiratory disease.12,13,16,24 A report from Vanamo and coworkers16 reviewed the long-term outcome (mean age at follow-up: 29.6 years) of survivors of congenital diaphragmatic defects treated between 1948 and 1980. Eighty-three percent of these patients considered themselves normal. Seven patients (12%) had asthma and 4 (7%) had recurrent respiratory tract infection. Noteworthy, some of the patients included in this study had diaphragmatic eventration instead of CDH, making it difficult to extrapolate specific conclusions regarding the long-term outcome of CDH survivors. More recent reports on CDH survivors managed with advanced treatments suggest that they present a high prevalence of clinically relevant respiratory problems.10,14,15,18,19,21,25,26 Chronic lung disease has been reported in CDH survivors, but its incidence is unclear. In a 1-year follow-up study of 13 CDH survivors, all treated with ECMO, D’Agostino and coworkers15 found that 7 (54%) had chronic lung disease (defined as the need for bronchodilators, diuretics, or oxygen supplementation) or needed ventilatory support. The 3 infants requiring ventilatory support had a patch repair of the diaphragmatic defect. A similar prevalence of chronic lung disease was reported by Muratore and coworkers who analyzed 100 consecutive CDH survivors treated between 1990 and 1999.18 In their study, 16% of patients remained oxygen-dependent for 6 to 33 months after discharge, and 43% diuretic-dependent 1 to 30 months after discharge. In addition, 60% and 40% required bronchodilators and inhaled steroids, respectively, during the first year of life. Both the use of ECMO and prosthetic patch repair were significantly correlated with worse clinical outcome. Recently, Jaillard and coworkers19 found a 22% prevalence of chronic lung disease among CDH survivors at 2 years of follow up, with a higher prevalence in those patients requiring ECMO or patch repair. Therefore, patients treated with ECMO or requiring patch repair of the diaphragmatic defect appear to have a higher risk of developing pulmonary morbidity. It is possible that ECMO use and patch repair may be indexes of a more severe disease and the increased risk in these patients reflects the pathology of the disease. On the other hand, those patients treated with ECMO and/or patch repair are likely to have undergone “maximal” conventional treatment before switching to ECMO, and surgical repair and lung morbidity may have been induced iatrogenically, owing to aggressive techniques of ventilation and management. In CDH survivors, the severity of chronic lung disease may require prolonged ventilatory support and tracheostomy.8,11,19,26,27 The proportion of patients requiring tracheostomy ranges between 3% and 6%, and in some series the need for a tracheostomy seems related with a poorer prognosis.8,19,27 On the other hand, chronic lung disease tends to improve during the first year of life,14,15,29 accordingly, in studies with extended follow up,20-22 it is not reported.

135 CDH survivors suffer from recurrent respiratory tract infections in infancy and early childhood.15,16,21,22,31 Muratore and coworkers18 found a high prevalence of viral bronchiolitis in CDH survivors less than 3 years old, despite aggressive antiviral therapy. Since Respiratory Syncitial Virus (RSV) is the most frequent pathogen in these patients, they suggest active RSV prophylaxis in CDH survivors during the period of maximal exposure to the virus.18 Kamata and coworkers21 found recurrent pneumonia to be the most prevalent morbidity (39%) among 33 CDH survivors at a mean follow up of 11.4 years. Similar data are conveyed by Trachsel and coworkers22 who found a past history of pneumonia in 35% of CDH survivors at a mean follow up of 13.2 years, and by Okuyama and coworkers,31 who reported that 26% of their CDH survivors had recurrent pneumonia. Obstructive symptoms such as bronchospasm or wheezing are frequently reported sometime in the lives of CDH survivors,15-17,20,22,25 and a high proportion had been diagnosed with asthma.17,22,25 These symptoms are perceived to decline with ageing,17,22 although abnormalities in pulmonary function tests (PFT) persist. Actually, CDH survivors may have obstructive, restrictive, and combined (obstructive and restrictive) pulmonary function anomalies.12,13,16-18,20,22,32-36 In addition, they may have bronchial hyperreactivity to pharmacological challenges.16,35 PFT anomalies have been related to many causes. Marven and coworkers17 suggest that the reductions in expiratory flows are due to lower functional volumes rather than primary airway obstruction because when they corrected the flows for lung size no differences were seen from control subjects. Bronchial reactivity may have different explanations. It was suggested that it might stem from altered airway geometry or may be due to the association of gastroesophageal reflux, which is frequent in CDH survivors.16 Ijsseltin and coworkers35 compared respiratory outcome of CDH survivors with that of other children without CDH but requiring similar neonatal intensive care and found no differences in lung function between the two groups. In addition, the duration of mechanical ventilation tended to correlate negatively with spirometric findings. Similar data have been reported by Stefanutti and coworkers,20 who found a significant negative correlation between the duration of assisted ventilation and forced expiratory volume in 1 second. These data suggest that PFT anomalies, including bronchial hyperreactivity, are as much or more the result of artificial ventilation as of lung maldevelopment. Recently, Trachsel and coworkers22 found a significant association between PFT abnormalities and chest wall abnormalities, suggesting that, in CDH survivors, a decreased compliance of the chest wall may contribute to PFT abnormalities. During gestation, the normal lung develops from the 4th to the 16th week. There is successive branching of bronchi and pulmonary arteries from birth into childhood. Subsequent growth occurs by an increase in the number of alveoli. In CDH patients, most have pulmonary hypoplasia which affects both lungs, with a reduced number of airway gen-

136 erations and pulmonary arteries.37 In CDH survivors, lung hypoplasia persists as demonstrated by ventilation/perfusion (V/Q) radionuclide tests. In fact, V/Q scans invariably show abnormalities, mainly in lung perfusion.13,16,18,20,31,36,38-40 With repeated lung scintigraphy, pulmonary volume is reported to increase, whereas lung perfusion does not. Vascular and alveolar growth proceed hand in hand postnatally,41 and a few reports on lung morphology after neonatal repair of CDH describe an increase in alveolar size.42,43 This suggests that lung distension contributes significantly to the observed normalization of lung volume in CDH survivors and that compensatory alveolar multiplication remains, at best, incomplete. The value of V/Q scans in predicting future pulmonary outcome is still a matter of debate. V/Q scans were found not specific in foreseeing the development of obstructive airway disease in CDH survivors.18 Nonetheless, in the same study, lung scintigraphy was 86% sensitive in predicting obstructive lung disease, and recently, Okuyama and coworkers found V/Q scan performed in infancy to be a good indicator of subsequent pulmonary morbidity and nutritional status.31 Chest radiographs (CXR) are frequently abnormal in CDH survivors.16,18,20,32,36 These abnormalities are variable and include radiographic evidence of chronic lung disease, hyperlucency, hyperinflation, persistent lung hypoplasia, decreased pulmonary vascularity, presence of lung opacities, mediastinal shift, abnormal diaphragmatic profile, and recurrent herniation. Because CXR abnormalities, although subtle and with little correlation with clinical outcome, may influence medical history, they should be taken into consideration while following a CDH survivor. In particular, the presence of atelectasis, peribronchial thickening or pulmonary edema may suggest the need for aggressive medical treatment. Recurrent herniation is noted in up to 22% of CDH survivors30 and is a major sequela needing further surgical treatment. It is seen more frequently in those patients with very large defects and requiring patch repair of the diaphragm.26,30,44 Recurrent herniation usually presents before 3 years of age,26,29,30,45 and Moss and coworkers described a bimodal distribution of recurrence with 14% prevalence between 1 and 3 months and 28% prevalence between 10 and 36 months.45 Although most CDH survivors are clinically normal, many of them present subclinical abnormalities in their chest radiographs, lung scintigraphy, and/or pulmonary function tests. Whether these abnormalities will remain silent for all their lives or will manifest in the event of declining compliance (eg, from thoracotomy, scoliosis, surgery, or pneumonia) or at longer follow up is still unknown. Therefore, a careful respiratory follow up of these children into adulthood is warranted.

Neurological outcome A variable, but significant proportion of CDH survivors have neurological sequelae (Table 1), including develop-

Seminars in Pediatric Surgery, Vol 16, No 2, May 2007 mental delay, motor, cognitive, and behavioral disorders.11,15,23,25,28,30,46-49 Several factors are associated with neurodevelopmental outcome in CDH survivors. The need for ECMO seems related to a poorer neurological outcome. Some authors suggest that CDH patients treated with ECMO do less well than infants treated with ECMO for other reasons. Bernbaum and coworkers46 reported that, in a group of 82 ECMO survivors, patients with CDH had a significant developmental delay as compared with those requiring ECMO for other primary diagnoses. Other studies found no differences in neurodevelopmental outcome between CDH and non-CDH patients treated with ECMO. Stolar and coworkers reported that, in 51 ECMO survivors, “the diagnosis of ECMO did not contribute to neurological risk.”50 Similar findings were later reported by Nield and coworkers49 and by Jaillard and coworkers,51 who found no differences in neurodevelopmental outcome in 130 and 36 ECMO survivors, respectively, between infants treated with ECMO for CDH and for other diagnosis. McGahren and coworkers,47 comparing the neurodevelopmental outcome of 12 patients with CDH requiring ECMO with that of 25 CDH survivors who did not require ECMO, found a higher prevalence of neurodevelopmental deficits and abnormal neuroimaging anomalies in patients treated with ECMO, suggesting that the use of ECMO may bring about an increased risk of neurodevelopmental deficits. Whether this reflects a more severe primary disease or is a consequence of a more aggressive treatment is unclear, and probably both are true. Actually, ECMO is employed in very sick babies who may be prone to hypoxic/ischemic brain injuries. On the other hand, ECMO may be associated to an increased risk of neurological complications due to the need of anticoagulant treatment and ligation of the carotid artery in some. However, the higher prevalence of neurological sequelae in ECMO-treated CDH survivors was not confirmed in a subsequent similar study from Jaillard and coworkers,51 who found no differences in neurological outcome between 18 CDH survivors treated with and 33 without ECMO. In infants with CDH, a prolonged neonatal hospitalization has been associated with a poorer neurological outcome.23,49 The length of hospital stay may reflect the severity of the primary disorder, thus supporting this as a major factor in the development of neurodevelopmental disorders in CDH survivors. Cortes and coworkers23 found that, in 16 CDH survivors, the need for oxygen supplementation at hospital discharge was the most consistent predictor for neurodevelopmental outcome, further supporting the role of primary disease severity. A low socio-economic status is another factor associated with a worse developmental outcome in CDH survivors.49,50 These findings are similar to those reported in preterm infants.52,53 Advantaged environments can reduce the influence of medical risk factors, whereas poor environments and lack of social support can amplify the impact of perinatal risks.54 Last but not least, recent findings suggest that in CDH patients surgical intervention itself can reduce cerebral blood volume and oxygenation as

Bagolan and Morini Table 1

Long-Term Follow Up of CDH

137

Prevalence of gastroesophageal reflux, antireflux surgery, and neurodevelopmental sequelae in long-term CDH survivors

Author

Pts

Stolar et al, 199067 Koot et al, 199372 Van Meurs et al, 199330 Nagaya et al, 199474 Lund et al, 199411 D’Agostino et al, 199515 Kieffer et al, 199573 Rais-Bahrami et al, 199570 Stolar et al, 199550 Wischermann et al, 199534 Vanamo et al, 199616 Naik et al, 199677 McGahren et al, 199747 Schoeman et al, 199971 Huddy et al, 199992 Muratore et al, 200118 Bétrémieux et al, 200278 Jaillard et al, 200319 Davis et al, 200425 Hedrick et al, 200427 Cortes et al, 200523 Colvin et al, 200584 Crankson et al, 200628 Chiu et al, 200610 TOTAL

17 31 18 86 33 16 74 33 25 45 60 15 37 8 13 121 12 51 27 19 16 37 31 38 863

Follow-up (mos)

ECMO

GER (%)

Surgery for GER (%)

Neurodevelopmental sequelae (%)

32 6 8–72 6–120 5–72 0.6–12 36 24 31 7–360 355 6–36 3–120 2–32 24–84 12–120 12–72 24 ⬎12 0.7–88 24 24–156 6–108 36

Y N Y Y Y Y N Y Y N N Y Y Y N Y N Y Y Y Y N Y Y

17 52 17 12 — 81 62 76 — 13 63 13 — 67 23 60 50 27 52 47 62 27 26 45 39

0 16 0 8 18 12 32 — — — 18 13 22 62 15 21 — 6 15 11 60 5 6 32 19

— — 42 — 45 46 — — 44 — — — 35 — — — 8 12 19 21 54 17 23 32 31

Abbreviations: Pts, patients; Mos, months; ECMO, extracorporeal membrane oxygenation; Y, yes; N, no; GER, gastroesophageal reflux.

shown by near-infrared spectroscopy, being potentially harmful to neurocognitive development.55,56 Neurodevelopmental outcome is likely to improve with ageing as supported by the fact that studies with longer follow up tend to demonstrate a more normal neurological outcome.57 Accordingly, Nield and coworkers49 found that a higher proportion of CDH survivors were in the at-risk category of developing abnormal neurological outcome at 1 to 2 years of follow up than at 3.5 years of follow up. This may reflect an early medical fragility of this group with an improvement of neurological status over time. Alternatively, it may depend on a selection bias from an increased death rate among the neurologically impaired. Sensorineural hearing loss (SNHL) represents a peculiar form of neurological sequela in CDH survivors.11,23,25,47,58-62 The prevalence is very variable, ranging form nothing19 to 100%,60 and this variability may be due to differences in definition of significant hearing loss among studies. SNHL is found in CDH survivors treated with ECMO25,58-61 and without ECMO,58,60,62 suggesting that the use of ECMO is not the only predisposing factor for SNHL. CDH survivors are exposed to a number of other potential predisposing factors, including the use of ototoxic medications such as diuretics, muscle relaxants, and antibiotics, and prolonged mechanical ventilation with high oxygen tensions. Walton and coworkers63 found that, in 51 persistent pulmonary hypertension survivors, duration of hyperventilation was the only factor associated with SNHL development. Fligor and

coworkers, in a cohort of ECMO surivors, found that a lengthy (⬎14 days) course of aminoglicosides was significantly correlated with the development of SNHL.61 In addition, CDH patients were more prone to SNHL than their non-CDH counterparts.61 Therefore, CDH survivors are at high risk of developing SNHL, due to both the severity of primary disease and the exposure to numerous risk factors. Because SNHL may be the cause of speech delay and is usually progressive in nature, a stringent audiological follow up is mandatory to detect as soon as possible SNHL development, thus reducing its consequences. Neuroimaging abnormalities are an important issue in CDH survivors because they are relatively frequent, although their meaning is unclear. In a study on 18 CDH survivors, all treated with ECMO, Van Meurs and coworkers found that 76% had neuroimaging abnormalities at computed tomography or magnetic resonance performed soon after extubation.30 However, no obvious correlation was found between early neuroimaging status and long-term neurodevelopmental outcome.30 Hunt and coworkers,64 reviewing a 1-year series of CDH patients not treated with ECMO, found that 8 of 10 CDH short-term survivors had neuroimaging abnormalities. Interestingly, 5 of these patients with cerebral abnormalities on magnetic resonance had a normal cranial ultrasoud scan, suggesting a poor sensitivity of the latter for white matter injury. However, this study comprises only 10 patients and has no long-term follow up, not allowing definitive conclusions on the rela-

138 tionships between neuroimaging anomalies and long-term neurological outcome. A recent study from Cortes and coworkers found that neonatal brain imaging did not correlate well with neurodevelopmental status.23 Yet, they used different imaging modalities in their patients and concluded that the lack of correlation between neuroimaging and clinical status may depend on the varying sensitivity of the different modalities in detecting brain damage. As seen, most CDH survivors have multiorgan problems that require prolonged recovery periods. As a result, it is not surprising that initial development may be delayed. The available data suggest that neurological sequelae tend to improve with time and with the resolution of other organ disorders. Therefore, long-term neurological follow up is recommended to early detect neurological deficits and to provide adequate support to the evolving child.

Gastrointestinal outcome Gastroesophageal reflux (GER), with all its associated nutritional (and pulmonary) consequences, is the most common sequela.15,65-70 This condition was rarely referred to in association with CDH before 1990,66 but recent studies have shown that GER is commonly found in short- and long-term survivors of CDH.69,70 A review of the incidence of GER among CDH patients in different studies is reported in Table 1. These data suggest that nearly 40% of babies operated on for CDH will have symptomatic GER, half of which require antireflux surgery. The incidence of GER is very variable in institutions both with and without ECMO (Table 1). The variability in the reported incidence of GER may also depend on the diagnostic method used: pH monitoring, upper gastrointestinal (UGI) contrast study, or clinical history of GER. D’Agostino and coworkers noted that 81% of CDH survivors had symptoms of GER after repair, but only 50% remained symptomatic at 1 year of age.15 In contrast, Vanamo et al. found that 18% and 63% of 60 survivors with CDH presented symptoms suggestive of GER at early and late (29 years) follow up, respectively. The authors could not find any significant correlation between the initial size of the diaphragmatic defect and late GER. Likewise, Cortes and coworkers reported that the proportion of patients requiring GER medications was 44% and 63% after diaphragmatic repair at 1 year and 2 years, respectively.23 Many recent studies have emphasized the positive impact of the new CDH management strategies on survival whereas only a few analyzed the long-term outcome of patients treated with these new strategies compared with the classical ones. Chiu and coworkers retrospectively reviewed their CDH patients comparing two different groups: babies treated with conventional ventilation (CV) and those with gentle ventilation (GV). They found trends toward increased incidence of GER disease (GERD) among babies managed with GV (45%) compared with those managed with CV (33%). Antireflux surgery also showed a

Seminars in Pediatric Surgery, Vol 16, No 2, May 2007 similar trend in this series: 32% in the GV-treated and 21% in the CV-treated patients. Implementation of GV techniques has probably decreased mortality in infants with CDH, but this is associated with a documented increase in nutritional morbidity among survivors.10 Cortes and coworkers reported in 2005 a prospective follow up of 16 babies with severe CDH (liver up into the thorax and low lung to head ratio) randomly treated with tracheal occlusion (7 patients) or with standard perinatal care (9 patients). Regarding patients requiring GER medications, the authors found no difference between those treated with tracheal occlusion and those with standard care. The proportion of patients with GER was significant, with a trend toward an increasing incidence at 20-year (63%) compared with 1-year (44%) evaluations. Other authors noted that the incidence of GER was higher among patients requiring ECMO than among other CDH infants.19,69-71 Despite its frequency, the pathophysiology of GER remains unclear. Anatomical factors associated with CDH that may contribute to GER onset are the following: 1) mediastinal shift and compression during fetal life may disturb the normal development and mobility of the intrathoracic esophagus, leading to chronic ectasia and impairment of lower esophageal sphincter function67; 2) kinking of the esophagus at the gastroesophageal (GE) junction may be responsible for esophageal obstruction and in utero polyhydramnios, thereby increasing esophageal ectasia67; 3) formation of the GE junction may be abnormal, particularly when the whole stomach is herniated into the chest during organogenesis (recent reports suggest that the presence of an intrathoracic stomach at surgery is associated with GERD72,73); 4) deviation to the affetcted side and shortening of the abdominal esophagus (with consequent hiatal hernia) before the lung is well expanded74; 5) His angle deformation at the diaphragmatic crus, with development of hiatal hernia, secondary to closure of the diaphragmatic defect with excessive tension57; 6) elevated pressure gradient across the hiatus following an increased intrabdominal pressure along with reduced intrathoracic pressure associated with elevated respiratory work57,75; 7) absence of perihiatal diaphragm, recurrence of CDH.69,73 Predictors of GERD are controversial. A few authors noted a correlation between GER and preoperative position of the stomach and of the left liver lobe in the chest, presence of an hernial sac, and size of defect.73 The most frequently reported predictor of antireflux surgery is the need of diaphragmatic patch repair.19,65 In Muratore’s series,65 37% of CDH survivors needed an upper GI study for severe clinical reflux unresponsive to medical treatment, 93% of patients with positive GI studies for reflux had antireflux surgery performed. Jaillard et al. found GERD as the main associated complication in 18% of 85 newborn infants with growth failure after CDH repair: they propose primary antireflux surgery at the time of a large diaphragmatic defect repair.19 Untreated GERD has been also recognized as responsible for “unexplained” late death among such patients,57 as observed in 2

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139

of 31 survivors of Crankson’s series.28 The impact of GER on these patients mandates close follow up, with appropriate use of medical/surgical antireflux treatment and optimal feeding to enhance nutritional state and growth. Infants operated on for CDH, in which pulmonary function is often compromised, need prompt diagnosis and eventually surgical treatment of GERD.10,19,65 Despite adequate caloric intake (even via gastrostomy tube feeding in a few babies), a significant number of CDH survivors show evidence of failure to thrive (FTT) and remain below the 25th and even the 5th percentile for weight.10,65,76 As previously noted, GERD may be one of the etiologies. Nevertheless, many other factors are implicated in the pathogenesis of growth failure in CDH patients, such as chronic lung disease with the consequential need of fluid or volume restriction, increased respiration work, and oral aversion (OA). The reported incidence of CDH patients with long-term persistent morbidity as well as FTT and OA is reported in Table 2. These data suggest that 60% of CDH survivors are likely to have some type of persistent morbidity, with FTT being present in more than 30% of cases, most of which will require “aggressive” treatment with gastrostomy tube placement. In Naik’s series of 15 cases,77 duration of ventilatory support (more than 10 days) had a 90% sensitivity and 100% specificity, with a positive predictive value of 100% for morbidity at follow up. Recently, Chiu and coworkers, comparing morbidity of CDH patients treated with conventional ventilation and those treated in the gentle ventilation era, reported that the only type of morbidity which was statistically higher in survivors was the need for

gastrostomy tube: 34% in gently ventilated compared with 8% of conventionally ventilated patients.10 The group from San Francisco, in their small selected group of left CDH at 1 and 2 years outcome, also reported severe growth failure with considerable catch up growth by age of 2: 71% versus 27%.23 Nevertheless different management protocols at different institutions still significantly affect morbidity rates among survivors, and this must be taken into consideration when comparing different sets of data. The etiology and management of either OA or FTT is still controversial.66 They may be related to the severe anatomic defect, the prolonged need for mechanical ventilation and hospitalization, as well as chronic lung disease. Bétrémieux, in his 12 CDH survivors who did not required prolonged ventilation or home oxygen and without bronchopulmonary dysplasia, found that growth was absolutely normal.78 In contrast, Muratore and coworkers report that FTT and OA were both significantly predicted by the need for oxygen at discharge, whereas duration of ventilation significantly predicted OA and consequent need for gastrostomy tube. In addition, linear regression analysis found that the need for ECMO was predictive of FTT, whereas patch requirement was more specifically predictive of subsequent need for gastrostomy tube65; out of the 121 consecutive patients followed up in this exhaustive series, one-quarter presented OA and one-third eventually needed gastrostomy tube placement. The rate is consistent with that of Jaillard and coworkers.19 In contrast, no significant predictor of FTT was found by others.23 It has been speculated that prolonged endotracheal intubation may be responsible for a delay of

Table 2 Prevalence of overall persistent morbidity (PM), failure to thrive (FTT, defined as weight ⬍25th or 5th centile), oral aversion (OA), need for gastrostomy tube (GT), bowel obstruction (BO), pectus deformities (PD), and vertebral deformities (VD) in long term CDH survivors Author

Pts 33

Falconer et al, 1990 Lund et al, 199411 D’Agostino et al, 199515 Nobuhara et al, 19965 Vanamo et al, 199616 Naik et al, 199677 Schoeman et al, 199971 Huddy et al, 199992 Muratore et al, 200118 Bétrémieux et al, 200278 Jaillard et al, 200319 Davis et al, 200425 Hedrick et al, 200427 Cortes et al, 200523 Colvin et al, 200584 Crankson et al, 200628 Chiu et al, 200610 Chiu et al, 200610 Mukhtar et al, 200690 TOTAL

19 33 16 — 60 15 6 13 121 12 51 27 19 16 37 31 38 24 16 552

Follow-up (mos) 72–132 5–72 0.6–12 — 355 6–36 2–32 24–84 12–120 12–72 24 ⬎12 0.7–88 24 24–156 6–108 36 36 60–120

PM (%)

FTT (%)

OA (%)

GT (%)

BO (%)

PD (%)

VD (%)

— — 80 — — 66 — 63 — 7 45 75 52 — 61 87 — — — 60

— 39 — — — 27 — 38 56 0 18 37 — 27 19 23 58 54 — 33

— — — — — — — 15 25 17 25 — — — 16 — — — — 20

— — 69 — — — — 23 33 — 7 15 — 44 — — 34 8 — 29

— 18 75 — 20 13 25 — — 8 — 11 — — 37 23 — — — 26

21 33 — 21 48 — — — — — — — — — — 10

11 12 — 10 27 — — — — — 4 — — — — 3

Abbreviations: GV, gentle ventilation; CV, conventional ventilation..

29 46 50 31

25 13

140 swallowing reflex development.65 This observation is supported by the finding of an impaired swallowing reflex in adult patients requiring prolonged intubation79 and a higher incidence of dysphagia in pediatric patients after cardiac surgery and intubation for more than 7 days.80 Management of these patients is difficult; some authors favor “aggressive” and early intervention to prevent FTT and subsequent developmental delay,65 whereas some others are very restrictive in performing gastrostomy, as it is generally thought to worsen OA.19 Whether early oral rehabilitation could prevent such problem remains speculative, but prevention with feeding protocols similar to those recently described for preterm babies81,82 should be considered. Management of FTT and OA includes increased caloric intake, fluid/volumes restriction, use of diuretics, fortification of feedings, and placement of a gastrostomy tube may be required in patients with growth failure despite the use of specific formulas or foods. Finally, when all other treatment options fail, exclusion of GER/GERD and its medical or surgical treatment, is warranted. Other gastrointestinal surgical problems resulting in significant chronic morbidity include intestinal adhesions with obstruction, volvulus (secondary to malrotation), intestinal perforation, and ischemia.11,15,28,71,78,83,84 Intestinal obstruction has been reported in 2.2% of patients who had laparotomy in childhood, in 8.3% of those who had Ladd’s procedure for malrotation, and in 4.2% to 75% of CDH survivors.11,15,85,86 The incidence of intestinal obstruction among CDH survivors is reported in Table 2. Bowel obstruction was the most frequent cause of reoperation in the Lund’s experience,11 and was found even among patients treated with a trans-thoracic approach.83 Adhesion obstructions are found in 40% of patients following antireflux surgery, sometimes responsible for sepsis syndrome and death.71 Several mechanisms may contribute to the higher rate of intestinal obstruction in CDH survivors: malrotation, and possible intestinal kinking, prolonged intestinal paralysis, increased abdominal pressure (and intestinal hypoperfusion) with subsequent further hypomotility of the bowel. Vanamo and coworkers found a significant correlation between length of initial hospital stay and later bowel obstruction.83 All of these findings indicate that there is considerable long-term gastrointestinal morbidity among patients with CDH, the major problems being GER (and its consequences), FTT, and late bowel obstruction.

Musculoskeletal outcome The close relationship between development of the lung, diaphragm, and thoracic cage is highlighted by the frequency of musculoskeletal abnormalities87-89 in children who have undergone CDH repair. Chest asymmetry and pectus deformity are the most commonly described, followed by vertebral deformity (scoliosis and kyphosis).10,11,16,19,22,33,58,83,90 Because chest wall and spinal de-

Seminars in Pediatric Surgery, Vol 16, No 2, May 2007 formities develop throughout the entire growth period, their true incidence may be defined only when growth is stopped. For this reason, surveillance of survivors into adulthood is recommended.91 The reported incidence of skeletal morbidity is summarized in Table 2. These data suggest that more than 40% of CDH survivors may suffer from some musculoskeletal abnormality. Some authors suggested that these deformities may be due to an excessive tension of the diaphragmatic repair,11,26,91 others to thoracotomy for the repair of the defects91 or to the smaller thoracic cavity with smaller lung in the affected side,91,92 as supported by experimental models.93 Large diaphragmatic defects were significantly more frequently associated with both pectus and vertebral deformities, whereas ventilatory impairment, studied with radiospirometry, was more specifically associated with scoliosis.91 Jaillard found scoliosis only among patients treated with ECMO.19 The high prevalence of significant scoliosis and the more even distribution between males and females (6:10) and right:left convex thoracic curves (6:10)91 indicate that, in CDH survivors, the etiology of scoliosis is different from that of idiopathic scoliosis, where male:female is 10:1 and 90% of the curves in the thoracic region are convex on the right side.94 Recently, Chiu and coworkers found a significant number of patients referred for scoliosis in the conventionally ventilated cohort than in the gently ventilated cohort (46% versus 29%), suggesting that primary repair of large diaphragmatic defects in the first group probably contributed to the long-term skeletal deformities, whereas the tension-free repair using a patch was probably beneficial in preventing these problems.10 Most of these patients can be managed without surgical intevention,10,27 and 83% consider themselves healthy.91 Therefore, they require a careful follow up to prevent functionally detrimental deformities.

Quality of life As previously stated, CDH patients face life-threatening morbidity during the neonatal period and some CDH-related symptoms during their first years of life.34,58,95 Diseasespecific symptoms, not unique to CDH patients, are more frequently reported in CDH patients than in the general population. Poley at al96 found a significantly higher symptom score for CDH patients under the age of 19 (mean score 6.8) than for their contemporaries in the control group (mean score 4.9). Moreover, analyzing 167 CDH patients (age range 1 to 42 years), they reported that, compared with the general population, a significant number of patients under the age of 20 was admitted to hospital (17% versus 4%) and consulted a physiotherapist (13% versus 7%) during the last 12 months. A significantly larger proportion of the older CDH patients (between 20 and 45 years of age) consulted a general practitioner during the last 12 months (96% versus 74%) and used prescribed medication during the last 14 days (41% versus 10%). On the opposite, the

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141

share of CDH patients younger than 20 years of age for whom medication is prescribed was found even smaller than that in the general population. Health state evaluation, scored 0.92 for CDH patients between 5 and 15 years and 0.91 for adult CDH patients, was not found different from the reference scores for general population (0.93 both in adults and children). Thus, taking medical consumption as an indicator of quality of life, the CDH patients seem lower than that of the general population. Despite this, the overall quality of life of these patients does not differ from the general population.96 Investigating short- and long-term health-related quality of life of 111 survivors of CDH, the group from Rotterdam96 concluded that quality of life is favorable in these patients even if symptom score showed a clear decrease over the years in the control group which did

Table 3

not match the pattern found in CDH patients. Compared with reference data, the quality of life of patients aged 1 to 4 was poor, whereas in the patients aged 16 years and over, no difference with the general population was found. Significant difference was defined in 5 domains: stomach, eating problems, positive emotions, vitality, and motor problems. Surprisingly, no clear evidence of a difference in the domain of “lungs” was found. One possible explanation is that, particularly in the past, a major “selection” took place in the first year of life, due to severity of lung hypoplasia and persistent pulmonary hypertension in these babies. Treatment of CDH was recently found having a favorable cost-effectiveness and, considering the growing importance of this issue, this is an encouraging and important consideration.97 The average costs of a treatment including

Proposed follow-up schedule for CDH survivors

3 months Auxological (weight, ⫹ length, head circumference) Respiratory CXR ⫹ PFT

6 months

9 months

⫹

⫹

CXR (PFT if obstructive/ restrictive lung disease)

CXR (PFT if obstructive/ restrictive lung disease)

12 months ⫹ CXR ⫹ PFT

If symptoms or If symptoms or If symptoms or UGI. If positive: Gastrointestinal signs of GERD signs of GERD signs of GERD pH metry/ (UGI, pH metry/ impedance impedance monitoring monitoring, and gastric gastric scintigraphy scintigraphy) Cardiovascular (ECHO If abnormal before ⫹ ⫹ If previously and cardiological discharge or on abnormal, on follow-up) supplemental O2 supplemental O2 or symptoms and signs of PPH Neurodevelopmental If symptoms or ⫹ If symptoms or ⫹ previous previous abnormalities abnormalities Hearing loss If previous ⫹ ⫹ ⫹ anomalies If onset of new If previous If previous Brain imaging (USS/ If previous clinical anomalies or anomalies or CT/MRI) anomalies or abnormalities abnormal abnormal abnormal neurological neurological neurological findings findings (USS) findings (USS) Orthopedic If indicated If indicated If indicated ⫹

18 months ⫹ CXR (PFT if obstructive/ restrictive lung disease)

If symptoms or signs of GERD

24 months (yearly until 14 years of age) ⫹ CXR (PFT at 6 years of age and yearly thereafter if obstructive/ restrictive lung disease) If symptoms or signs of GERD

If previously If previously abnormal, on abnormal, on supplemental supplemental O2 or O2 or symptoms and symptoms and signs of PPH signs of PPH If symptoms or ⫹ previous abnormalities If previous ⫹ anomalies If onset of new If previous clinical anomalies or abnormalities abnormal neurological findings If indicated ⫹ (and yearly until adulthood if indicated)

Abbreviations: CXR, chest X-rays; PFR, pulmonary function tests; UGI, upper gastro-intestinal contrast study; GERD, gastro- esophageal reflux disease; ECHO, cardiac ultrasound; PPH, persistent pulmonary hypertension; USS, ultrasound scan; CT, computed tomography; MRI, magnetic resonance imaging.

142 ECMO in Europe was recently estimated of 35,718 €, apparently not much different than the costs (32,376 €) of a treatment without ECMO. Others found that direct medical costs are likely to be as high as $98,000 per survivor without and $365,000 per survivor with need of ECMO, respectively.98 ECMO is widely believed to improve survival rates in newborn babies with severe respiratory failure. At the same time, pulmonary hypoplasia and iatrogenic ECMO morbidity may lead to lower quality of life of ECMO survivors. In conclusion, CDH survivors may have a variety of long-term sequelae, which may require prompt intervention. As a consequence, they should be closely followed up in a dedicated outpatient clinic, ideally until adulthood. Here, we propose a possible follow-up schedule (Table 3) for CDH survivors, based on the clinical findings reported in long-term follow-up studies and on our personal experience. The proposed schedule may be changed for patients requiring more strict follow up with closer evaluations over time. Although CDH is responsible for considerable symptoms early in life, the vast majority of CDH survivors ultimately enjoy healthy lives. Future efforts should be done to find ways to improve quality of life in youngest children.

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