Seminars in Pediatric Surgery 23 (2014) 278–282

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Seminars in Pediatric Surgery journal homepage: www.elsevier.com/locate/sempedsurg

Congenital diaphragmatic hernia: Where and what is the evidence? Paul D. Losty, MD, FRCSI, FRCS(Ed), FRCS(Eng), FRCS(Paed), FEBPS Department of Paediatric Surgery, Alder Hey Children's Hospital NHS Foundation Trust, University of Liverpool, Liverpool, UK

a r t i c l e in f o

Keywords: Congenital diaphragmatic hernia CDH Foetal therapy FETO ECMO iNO Sildenafil Surgery Long-term outcomes Animal models Genetics

abstract Congenital diaphragmatic hernia (CDH) retains high mortality and morbidity due to lung hypoplasia, pulmonary hypertension and severe co-existent anomalies. This article offers a comprehensive state-ofthe-art review for the paediatric surgeon whilst also describing key contributions from the basic sciences in the search to uncover the cause of the birth defect together with efforts to develop new and better therapies for CDH. & 2014 Elsevier Inc. All rights reserved.

Introduction A few years ago, paediatric surgeons, neonatologists, foetal medicine specialists, genetic experts, scientists and CDH parent support organisations from many countries attended an international conference in Rome, Italy. Delegates witnessed an excellent two-and-half day meeting held at the congress venue in the nearby vicinity of the Spanish Steps. The objectives of the conference were clear for all invited guest speakers and key participants: “To review current progress whilst crucially addressing the evidence base of varied management strategies including the latest ‘breaking news’ together with advances in the field.” This article is based (in part) on the invited lecture delivered by the author. Relevant work published since the Rome meeting is also included to provide the reader with a state-of-the-art 2014 update. CDH is a lethal birth defect (1 in 3000 live births), which can be highly unpredictable. Paediatric surgeons working in clinical practice for many years will have witnessed, e.g., “small-for-date” or premature CDH babies survive (why?), whilst those considered “healthy term” low-risk newborns with CDH die from respiratory distress or pulmonary hypertension as a result of inadequate lung development. CDH is therefore an enigmatic condition and unsolved problem.1 Advances leading to modest improvement(s) in survival have evolved from timely in utero diagnosis, newborn delivery at “high-volume” centres co-ordinated by multidisciplinary teams, along with the wider deployment in institutions worldwide of permissive hypercapnea strategies/“gentle

E-mail address: [email protected] http://dx.doi.org/10.1053/j.sempedsurg.2014.09.008 1055-8586/& 2014 Elsevier Inc. All rights reserved.

ventilation” to avert fatal pulmonary barotrauma.1 National and international CDH registries provide vital repositories for the paediatric surgical community with decisive publications helping benchmark a hospital or unit's team performance alongside providing contemporary data that may be used to determine practice variation, e.g., prenatal CDH risk categorisation, accurate case selection and recruitment (if appropriate) for foetal intervention in clinical trials and ongoing audit of hospital mortality/ morbidity metrics including examining rate(s) of patch failure, revisional surgery and deciding which patients are perhaps best suited for minimally invasive operative repair.1,2

The foetus with CDH Accurate prenatal diagnosis of CDH is now possible in many centres worldwide with detection rates steadily approaching 80%.1 All cases should be referred to a specialist unit for full risk assessment. Prenatal diagnosis affords the opportunity for counselling by an experienced MDT team, which must include a paediatric surgeon, neonatologist, midwife and obstetrician. Delivery (if parents opt for continuation of pregnancy) is scheduled with induction of labour and vaginal delivery as near term as possible ideally at 38 weeks to avoid spontaneous onset of labour, which may prove hazardous for the CDH baby if birth occurs at a remote community hospital. Studies from Canada and Scandinavia strongly support the concept of management at high-volume centres (treating more than 5–6 CDH cases/year) with survival at such institutions notably better.3,4 Prenatal detection raises the debate of foetal risk assessment, survival and outcome(s). Detailed

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sonography and echocardiography with or without foetal MRI aim to exclude associated abnormalities most notably congenital heart disease and chromosomal anomalies. Expectant mothers should be offered amniocentesis with karyotyping. In foetal centres, imaging should record the laterality of the CDH defect, presence or absence of liver herniation (“liver up”), stomach in the chest and a true estimate of the observed:expected lung head ratio (O/E LHR). In a robust systematic review and meta-analysis published in 2010 by the CDH research group in Liverpool, we convincingly showed that liver herniation correlated with poor prognosis (“liver up” 45%— survival vs “liver down”—74%—better outcomes P o 0.005).5 We further recommended grading the degree of liver herniation to refine outcomes further.5 The absolute measurement of the lung: head ratio (LHR) was first introduced as a new prenatal marker in 1996 by Harrison's group at UCSF.6 LHR was shown to be unreliable in a comprehensive study first presented at the BAPS International Congress meeting held in Stockholm, Sweden, in a research article delivered from Liverpool, later published in Ultrasound Obstetrics and Gynecology in 2007.7 Inaccuracies in predicting survival in the CDH foetus with absolute LHR measurement(s) were readily explained by the near-total absence of normative data available for LHR on the developing foetus without CDH.7 To address the weaknesses of LHR, the observed:expected O/E LHR was developed by Jani et al.8 taking into account key events associated with normal foetal growth as recommended by Liverpool researchers. The O/E LHR is now incorporated with a panel of other markers notably liver herniation as a prenatal scoring tool in selecting the “high-risk” foetus for intervention(s) before birth— see later. MRI lung volumetry may also be deployed to measure lung growth in the foetus. Along with the expanding potential (s) of imaging technologies to determine the status of the pulmonary vascular bed and the relationship to postnatal outcome(s) further large-scale evidence-based studies in the foetus with CDH are required.9

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ethical guidelines of a randomised controlled trial. In Liverpool, we provide ongoing care for CDH babies that have undergone the FETO procedure. The popular press, television media, internet, and CDH parent support organisations often widely advertise these high-profile cases. It is important and indeed morally correct that whilst having a duty to publicise latest innovations in health care, social media forums must also provide full and honest transparent information to expectant families. The FETO trial led by Deprest15 and participating international centres will be published shortly.

Delivery and postnatal management Delivery at a specialist centre is paramount to good out come(s).1,3,4 Induction of labour and vaginal delivery should be planned as close to term as possible—38 weeks to allow adequate pulmonary maturation. In ideal circumstances, “inborn” delivery should take place at a single-centre site fully equipped to resuscitate the newborn. Elective intubation and “gentle ventilation” to avoid barotrauma is aimed at stabilising labile physiology whilst awaiting delayed operative repair. There are no indications for urgent surgical operation of the diaphragmatic defect and the index case should be scheduled as a day time not “out-of-hours” operation.1 With the increasing antenatal detection rate of CDH, expert opinion regarding the best mode of delivery has been the subject of debate. In 2007, the CDH study group reported a marginal (nonsignificant) survival benefit for elective delivery by caesarean section.16 Further randomised studies are needed to draw any definitive conclusions. All babies should have a nasogastric tube promptly inserted to avoid gastric distension and timely vascular access secured to aid delivery of fluids and pharmacological agents including inotropes. Following early stabilisation, a full clinical examination is required to exclude associated anomalies. Chest radiograph confirming the diagnosis and echocardiogram is performed to screen for cardiac anomalies.

Foetal intervention and case selection

Postnatal diagnosis—“Late presenting CDH”

Excitement and great interest in foetal repair of CDH initially focused on the open operation of the diaphragmatic defect following maternal C-section hysterotomy. History and developments in foetal surgery are well described elsewhere.10 Trials were discontinued due to preterm labour and poor foetal outcome. Jay Wilson at Boston Children's Hospital then published a decisive report showing that hypoplastic lungs in the surgically induced lamb model of diaphragmatic hernia could be accelerated to grow by occluding the foetal trachea.11,12 Wilson et al's11 key contribution to the field led to spectacular refinement in the experimental surgical approaches used to treat human CDH.12 A decade later in 2003—Harrison et al.13 in San Francisco (working on the idea (s) first pioneered by Wilson) reported the first randomised controlled trial of open hysterotomy-guided foetal endoscopic tracheal occlusion (FETO). The UCSF group showed equivalent survival 73% in the TO group vs 77% survival (P ¼ 1.00) in “highrisk” foetuses also managed by conventional postnatal care (without TO).13 The trial steering committee halted the trial. Twelve years later—largely led by efforts of European foetal medicine specialists, a new minimally invasive operation termed percutaneous foetal endoluminal tracheal occlusion (FETO) is being subjected to a new randomised clinical trial.14,15 Selective entry criteria for the “high-risk” isolated CDH fetus now require an O/E LHR less than 27–28% with liver herniation (termed “liver up”) being incorporated with trial entry. At the time of writing FETO is a much debated experimental procedure. It is recommended by the author that referral to UK, European, and North and South American centres should only be offered within the strictest

Despite antenatal imaging, some 20–30% of patients with CDH may remain undetected until after delivery. Such cases may present in the immediate newborn period or first few days after birth whilst others may remain asymptomatic until later life. Symptoms here may include mild respiratory distress or feeding problems. Delayed presentation may occur with small diaphragmatic defects in which there is little or no herniated bowel at birth. These infants are at a potential risk for gut infarction from incarcerating thoracic viscera through a small diaphragm defect.1 Clinical examination may reveal bowel sounds on chest auscultation. There may be signs of decreased air entry on the affected side and rarely mediastinal shift. Diagnosis is often made on a chest radiograph but may require an upper gastrointestinal contrast study for further confirmation.

Stabilisation “Gentle” ventilation has been one of the leading major advances in the management of CDH. It was designed (permissive hypercapnea) to reduce iatrogenic lung injury from barotrauma. Wung et al.17 introduced this novel concept characterised by preservation of spontaneous ventilation, permissive levels of hypercapnea and avoidance of high inspiratory airway pressures (ideally not exceeding 25 cmH2O). A number of centres, including Liverpool, have steadily reported improving outcomes (more than 80% survival) by adopting this approach together with a much reduced need for ECMO.1,18 High-frequency oscillatory ventilation (HFOV) has been

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utilised in the perinatal management of CDH both as a “rescue therapy” prior to ECMO and as a primary ventilatory strategy in an attempt to reduce pulmonary barotrauma. There have been several reports of increased CDH survival with HFOV strategies.

Other therapies—ECMO, nitric oxide, and sildenafil ECMO has been traditionally deployed to treat respiratory failure and pulmonary hypertensive crisis in CDH following failure of conventional therapies. Throughout the 1980s and early 1990s, ECMO gained a steady momentum in the management of “highrisk” newborns with CDH. However, a UK multicentre led randomised controlled trial, and a more recent Cochrane review have failed to robustly demonstrate significant survival benefits with the deployement of ECMO in CDH.19,20 To this end, there has been a steady decline in the use of ECMO across many centres in North America, Europe, and elsewhere. Further efforts to treat pulmonary hypertension associated with CDH have included the use of inhaled nitric oxide (iNO) and the phospho-diesterase inhibitor, sildenafil. A large multicentre randomised controlled trial (NINOS) and a Cochrane review have also been unable to show significant sustained benefits with iNO therapy in CDH. In these published studies, iNO therapy did not (a) reduce the need for ECMO or (b) reduce CDH mortality.21 Sildenafil appears promising as a pulmonary vasodilator with successes recorded in small numbers of CDH case series.22 Drug bioavailability and therapeutic efficacy from erratic gut absorption may be a problem. Intravenous sildenafil has recently been tested with encouraging reports from Australia.23 Randomised controlled trials with stakeholders and partners in the pharmaceutical industry are required.

Surgery CDH was once regarded as a surgical emergency with operative repair performed early after delivery to improve ventilation by reducing the herniated viscera from the thoracic cavity. Currently, it is now widely accepted that preoperative stabilisation of labile physiology is paramount with delayed surgery scheduled following optimisation of respiratory and cardiac status.1 The classical operation is performed using a subcostal incision with the herniated contents returned to the abdominal cavity from the thorax and the defect in the diaphragm repaired. In the majority of cases (60–70%), a primary closure of the native diaphragm can be achieved. In the remaining patients, a prosthetic “patch” must be deployed to partition the defect. There are a number of different materials available to the surgeon, e.g., GORE-TEX or the biosynthetic substitute(s)—SURGISIS. Varied institutional reports have historically cited poor outcomes with patch repair with up to 50% patients in some centres requiring reoperation for recurrent CDH from prosthesis failure with patient growth.24 Experience from “high-volume” CDH programs in Philadelphia, USA, and Liverpool, UK, has been strikingly different with recent studies from these centres showing very low rates of patch failure ( o 10%) using GORE-TEX.18,25 We (like others) strongly believe that patch failure reflects a technical problem with its implantation at the primary CDH operation by the surgeon.18,25 Minimally invasive techniques (MIS) have become available for diaphragm repair. Benefits potentially include reduced postoperative pain and improved cosmesis whilst physiological derangement(s) during operation may be hazardous in fragile newborns. A systematic review undertaken by paediatric surgeons in Liverpool robustly showed that higher rates of hernia recurrence are a problem compared to good outcomes with the

classical open operation.1,26 To address these concerns surgeon case selection incorporating “low-risk” patients with smaller diaphragmatic defects should see high recurrence rates decline. Surgeons now rarely deploy the routine placement of an intercostal pleural drain after CDH repair. There are few (if any) true indications for a Ladd's operation in the “non-rotated” gut in the CDH patient with open or MIS repair. Such additional (and unnecessary) procedures increase patient morbidity and risk(s) for adhesive intestinal obstruction.1

Morbidity Chylothorax is the most common early post-operative complication.1 A pneumothorax will often present with a sudden deterioration in the cardiac and respiratory parameters of a ventilated patient too often with fatal outcome. Diagnosis of a pneumothorax on a routine post-operative chest radiograph should be made with extreme caution. The lung, on the side of a repaired CDH defect, is hypoplastic and will not fill the hemithorax giving the false impression of a pneumothorax to the inexperienced doctor. Post-operative effusions are common, e.g., chylothorax (28%) in some series.27 The majority of effusions are small and respond adequately to needle thoracocentesis. A recurrent troublesome chylothorax may require a pleural drain, octreotide, and a period of fasting and total parenteral nutrition with graded introduction of oral feeds with medium chain triglyceride (MCT) formula.27 At operations where the surgeon has had to be creative to achieve diaphragm closure with or without the use of a prosthetic patch for “near-complete” or total diaphragmatic agenesis, the author has found fibrin glue sealants—TISSEEL very helpful at reducing risk(s) of lymph fluid accumulation(s). Refractory collections should alert the surgeon to the possibility of a very rare disorder, which the author has encountered in caring for CDH patients over 25 years, notably co-existent congenital pulmonary lymphangioectasia—a uniformly fatal condition.28 Treatment here is futile and families should be counselled appropriately with care plans actively withdrawn. Diagnosis may be confirmed by high-resolution CT imaging and/or lung biopsy. Abdominal compartment syndrome (ACS) must be considered a risk in CDH patients where the volume of herniated abdominal contents returned to the abdomen is large often requiring patch repair and/or the primary diaphragmatic repair is under tension. The risk of developing ACS can be minimised by reducing intraabdominal pressure with the liberal use of an abdominal wall patch—“abdominoplasty.”1,18 Risk factors for recurrent CDH include large defect size and the need for a patch. Long-term outcome studies have reported reoperation is required in some 50% of patients having prosthetic patch repair. Technical factors with prosthetic implantation likely equate with early patch disruption and recurrent herniation.18,25

Reported outcome(s) and long-term follow-up Reporting of survival data in CDH shows outcomes ranging widely from 40% to 80% in different countries likely reflecting the variable quality of birth defect anomaly registries. However, outcomes from specialist centres including Liverpool (and other institutions) do show modest improvement(s) having witnessed our own unit exceed 85% survival to hospital discharge compared to a figure of only 50% seen in the early 1990s.18,29 Populationbased studies will claim these improvements may not include the full spectrum of antenatal losses and terminations, the so-called “hidden mortality” defined by Harrison et al.30 in the 1970s.

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Improving survival has created a “new population” with a corresponding increase in morbidity with the most vulnerable “highrisk” patients such as ECMO or FETO survivors contributing to cohort studies.1 These individuals require careful long-term follow-up in multidisciplinary specialist CDH clinics.1,31,32

Respiratory function Respiratory function may be impaired as a result of both failure of antenatal development (pulmonary hypoplasia) and postnatal lung injury (secondary to aggressive mechanical ventilation). The prevalence of chronic lung disease (CLD) amongst CDH survivors has been reported to be as high as 50% predominantly affecting “high-risk” cases requiring intensive resuscitation and ECMO. CLD and recurrent respiratory infections contribute greatly to failure to thrive. However, a number of long-term outcome studies have shown that pulmonary function can improve as survivors reach adolescence and adulthood.1,31,32

Gastroesophageal reflux (GER) The development of GER is a common problem in survivors, the impact of which is not just limited to feeding difficulty and reduced caloric intake but may also exacerbate any respiratory compromise from recurrent aspiration.2 GER may be managed with anti-reflux medication but a significant number of CDH survivors may require fundoplication to ameliorate symptoms and minimise morbidity. Studies from Toronto and Leuven have both defined groups at greatest risk which include ECMO survivors, babies having patch repair, i.e., large defects and FETO “liver up” cases.1,33,34 In Liverpool, with aggressive multidisciplinary team (MDT) medical management of GER only 10% of our patient population have required fundoplication.18 A number of mechanisms and theories have been postulated to explain the high prevalence of GER in CDH survivors notably defective diaphragm crura distorting the anatomy of the normally protective gastroesophageal junction barrier and the allied contributions from a shortened dysmotile oesophagus first proposed by Stolar et al.35 in 1990.

Neurodevelopmental Both motor and cognitive deficits are commonly seen in CDH survivors.1,36 Long-term follow-up studies report neurodevelopmental delay in 30–70% of patients. A recent North American study examining survivors in a multidisciplinary clinic at 3 years of life found that 73% of patients had variable degrees of motor delay (most commonly hypotonia and motor asymmetry), 60% had language problems, and 10% had profound sensory/hearing problems. It is thought that the neurological morbidity is largely secondary to recurrent episodes of neonatal hypoxia. Ventilator time and use of ECMO have been found to be statistically significant predictors of future neurological impairment (70% of patients with neurological delay had required ECMO in one study).36,37 Aminoglycoside therapy has also been strongly linked with sensorineural hearing loss.38

Basic science update future directions Steady progress in CDH research has been achieved through a better understanding of developmental lung biology including the wider recognition by many clinicians, not just paediatric surgeons of the robust validity of the varied experimental CDH models now

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available.1,39 The “dual-hit” hypotheses confirmed the origins of the primary and secondary insult to the primordial lung anlage and the later pathological contribution(s) from failed diaphragm closure and intrathoracic visceral herniation.40,41 Studies of normal and abnormal lung growth in organ culture systems have yielded crucial observations on growth factor signalling and processing in the nitrofen-induced hypoplastic CDH lung.42 The potential for growth factor therapy in CDH was first confirmed in studies from Liverpool over 14 years ago while the potential for prenatal hormonal therapy was also driven by Boston and Liverpool research groups in the 1990s with small- and large-scale CDH animal studies.42–44 To this end—an adequately powered randomised controlled trial evaluating prenatal corticosteroid therapy as medical therapy to rescue lung maturation is still required.1 It is of interest that the FETO procedure and randomised trial in progress incorporates elements of maternal betamethasone therapy. The vital contribution(s) of lung liquid and demonstration of airway persistalsis in dynamic organotypic culture experiments led the Liverpool group to identify for the first time the existence of a “lung pacemaker” responsive to growth factor(s) and calcium regulation.45 FETO with balloon occlusion and release exploits these biological principles. Stem cell biology work has also recently postulated “paracrine growth factor”-mediated signalling with amniotic fluid stem cell therapy with in vitro and in vivo experiments in the nitrofen model.46 These studies greatly mimic the FGF effects observed in hypoplastic lung organ systems by the research team in Liverpool well over a decade ago.42 The challenge(s) ahead—“can regenerative medicine technologies grow a new lung?”47 We will need to wait and see. Diaphragm substitutes as originally proposed by Fauza48 in the 1990s are an emerging reality with regenerative medicine tools. Regarding aetiology and pathogenesis, early studies by Cloutier and later basic science work led to a vitamin deficiency in human CDH being postulated with the crucial link of diaphragm–lung maldevelopment elegantly mastered in 2003 by John Greer with the “retinoid hypothesis.”49,50 Genetic advances are steadily moving the field forward with large-scale human gene studies led by Kate Ackerman and Pat Donahoe and co-workers in Boston.51–53 This energetic group at Harvard is helping to identify new candidate genes in the journey to uncover new avenues for therapeutic potential.51–53 Without the co-operation of many CDH parent support groups research programme(s) of this nature would be impossible. Further new discoveries are likely on the horizon. Watch this space.

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