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Updates in: Congenital Diaphragmatic Hernia

Merrill Mchoney

Department of Pediatric Surgery, Royal Hospital for Sick Children Edinburgh, Edinburgh, UK

 

Correspondence:

Merrill Mchoney

Department of Pediatric Surgery

Royal Hospital for Sick Children Edinburgh

Sciennes Road, Edinburgh, U.K., EH1 1LF

Phone: 0131 536 0661/0768

E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.

 

Abstract

Multiple teams are integrally involved in the management of the neonate with CDH. Standardised antenatal ultrasound scanning and lung measurements are used to aid prognostication, if uniformity in measuring and reporting are used. Antenatal MRI seems to have a specific role in providing additional data for selection of antenatal intervention, which would be best suited for prospective randomised studies to report on benefit and outcome.

Conventional ventilation with minimal pressures to achieve oxygenation and permissive hypercapnia are the mainstay of initial ventilation. Initial PaCO2 and oxygenation index on day 1 has been shown to predict outcome. HFOV is often used with clinical benefit alongside the other management strategies for PPHN, including iNO and cardiovascular support. Sildenafil infusion enhances iNO mediated vasodilatation, and has been shown to be associated with improved oxygenation and outcome. Other vasodilators (milrinone and prostaglandins) can be considered depending on clinical course. ECMO is reserved for patients with severe pulmonary or cardiac compromise refractory to other modalities.

No overarching clear cut indication of the best timing of surgery exist, other than the achievement of relative stability. Serial oxygenation index as well as other cardio-respiratoy parameters (blood pressure, ductal shunting, urine output and lactate levels) can be used to indicate stability, and timing. Although the thoracoscopic approach to CDH is used, the limits of 'intraoperative permissive hypercapnia’ in CDH have not been established, and needs investigating in this setting.

Long-term morbidity requires multiple specialist follow-up, as respiratory, cardiac, surgical, nutritional and feeding issues are present. Postoperative and discharge follow up is also multidisciplinary, and a one-stop clinic follow-up is becoming more popularly the gold-standard for outpatient follow up.

Keywords: congenital diaphragmatic hernia, antenatal, FETO, PPHN, surgery, ECMO, outcome, follow-up, multi-disciplinary

 

Introduction

Congenital diaphragmatic hernia (CDH) is characterised by a spectrum of developmental defects in the diaphragm and lung caused by disordered embryogenesis, resulting in incomplete fusion of elements giving rise to the diaphragm, with herniation of abdominal contents into the chest. Fusion of embryological elements between the 5th to 8th week of intrauterine life separates the abdominal cavity from the thoracic cavity. The last element to close is the pleuroperitoneal membrane, the site of the postero-lateral Bochdaleck hernia, the commonest (90%) form of CDH. Nine percent are found in an anterio-medial defect (Morgagni hernia). The remainder of cases comprise the relatively rarer forms of total absence of the diaphragm, absence of the central portion of the diaphragm, and oesophageal hiatal hernia. The incidence of CDH is 1 in 2,500 to 1 in 3,500 live births. Left-sided CDH is more common than right-sided, with a ratio of 6:1. Bilateral lesions are reported, but they are invariably fatal. Chromosomal abnormalities are found in 5–30% of cases (trisomy 18 and 13 are the most common). Increasing genetic investigation is demonstrating aberrant genetic defects in genes that are associated with both diaphragmatic development, lung and vascular budding[1]. Associated lung hypoplasia, vascular, and cardiac abnormalities lead to a high mortality (almost 50%). Abnormal development of the pulmonary vasculature leads to pulmonary hypertension and increased pulmonary vasculature reactivity. Patients can experience episodes of hypoxia, hypercapnia and persistent foetal circulation. Lung hypoplasia along with pulmonary hypertension is the most detrimental patho-physiological process that affects outcome. Emergent neonatal management is the most important influence on outcome; surgical correction has become a non-urgent secondary intervention.

The diagnosis can be made in the antenatal period, or can present in the early postnatal period with respiratory distress. CDH can present outside the neonatal period in patients with minimal physiological compromise. The mortality is negligible in this naturally selected group. Antenatal diagnosis and prognostication is used by some to guide antenatal intervention in patients with predicted poor outcome.

Surgical management has changed. Surgical morbidity is associated with the size of the defect and the need for patch repair. The advent of minimally invasive approach to surgical repair has developed, but requires expert management of acidosis and oxygenation. Long-term morbidity (affecting multiple systems) is also high, and can be related to both the underlying diagnosis as well as treatment.

This review will summarize the overall management of the patient with CDH in the antenatal and postnatal period, with emphasis on modern shifts in management, associated morbidity and long-term follow up.

Antenatal imaging and management

Routine antenatal ultrasound scanning detects approximately 50–85% of CDH. Lung to head ratio (LHR: contralateral lung area to head circumference) measured by antenatal ultrasound (US) has been used to predict the severity and outcome in CDH, and select for antenatal intervention. There is some good correlation between LHR and postnatal outcome, although some initial reports highlighted inconsistency in the predictive value of US measured LHR[2,3]. More recent data suggest differences in methodology and timing may have affected the prognostic value of US measured LHR. Therefore techniques to avoid inter-operator variation and to unify antenatal data has been suggested[4]; using the anteroposterior diameter at mid clavicle or a tracing method (preferably the latter as it seems to be most reproducible) should allow better correlation. Also LHR changes with gestational age[4] as lung growth is 4 times that of head growth in the 3rd trimester [5]. Therefore observed to expected LHR (O/E LHR) was developed. O/E LHR, and magnetic resonance imaging (MRI) total lung volume (TLV) have much more reproducibility and reliability than isolated LHR. The Antenatal-CDH-Registry Group measured the O/E LHR (by taking a transverse section of the foetal chest demonstrating the four-chamber view of the heart, and multiplying the contralateral lung area’s longest diameter by the longest perpendicular to it) and demonstrated that eliminates the effect of gestational age[6]. The O/E LHR is lower in foetuses with CDH compared to normal foetuses, and lower still in babies who die with CDH than those who survive[4]. There was however some overlap in values between survivors and non-survivors. The survival for left sided lesion related to O/E LHR with liver down was: ≤25%:30% survival; 26-35%:62% survival; 36-45%:75% survival; 46-55%: 90% survival and >55%: 85%survival[6]. O/E LHR using MRI may therefore be the gold standard for those offering antenatal intervention. It is worth noting that although LHR is predictive of mortality in CDH, it has not yet been strongly correlated with morbidity or PPHN [7].

TLV on foetal MRI may also have a role in providing more specific information to aid prognostic decision, and can be offered at 24 and 34 weeks gestation. Lung volume on MRI strongly correlates with lung area measured on US, and is predictive of outcome in left sided CDH [8], with the correlations of predictions seeming stronger earlier in pregnancy. Foetal MRI may yield additional useful information (e.g. % of liver herniation) and give better receiver operator curves for prediction[9]. Overall O/E TLV obtained by MRI scan correlates with US derived LHR, but without the operator dependant nature of measurements and maternal and foetal motion artefacts[8,9]. A recent meta-analysis confirmed the predictive nature of both US and MRI markers of lung development to predict the need for ECMO[7].

Although antenatal tracheal occlusion (TO) was suggested as a potential inducer of increased foetal lung growth in animal models, clinical benefits are not always clear from the research done to date. Foetal endoscopic tracheal occlusion (FETO) by endoscopic plugging in used in some centers in the management of cases with predicted severe CDH. There have been a few randomized trials reporting outcome of TO. Harrision et al [2] (24 cases, left CDH, liver up and LHR < 1.4) found some modest improvements in lung function but no discernible clinical benefit, and no differences in neurodevelopmental, respiratory, surgical, growth, and nutritional outcomes at 1 and 2 years of age. Contrary to that Ruano et al [10] (41 cases any side; LH< 1.0, liver herniation and no other detectable anomalies) and found a significant 6-month survival advantage associated with antenatal plugging (10/19 (52.6%) infants in the FETO group and 1/19 (5.3%) controls survived). Methodological differences in both studies which may account for the different outcomes. A recent meta-analysis of 5 studies (1 RCT) with 211 cases concluded that FETO improves survival in isolated CDH with severe pulmonary hypoplasia[11]. Further studies are needed to clarify the patient groups that may benefit from this intervention.

It would seem from the data (in terms of the best prognostic features, group and indication for antenatal intervention) that ongoing enrolment into FETO would be best suited for prospective randomised studies to report on benefit and outcome. One ongoing trial in Europe aims to enrol patients in with severe hypoplasia (O/E LHR <25%) and randomized to FETO. The acronym for the trial is TOTAL (Tracheal Occlusion To Accelerate Lung Growth, www.totaltrial.eu).

Post natal management

Emergent neonatal resuscitation at birth with immediate endotracheal intubation and mechanical ventilation using conventional ventilators is the initial respiratory support given. The suitability of cenventional ventilation as the initial mode of respiratory support has been confirmed in a recent trial[12]. Level of the initial PaCO2 can give predictive indications of outcome in CDH and can be considered a biomarker of successful management[13]. Initial PaCO2 in non-survivors at 30 days was higher than survivors, and infants who remained hypercarbic post resuscitation had a worse outcome than those who resuscitated to a normal PaCO2[14]. Best oxygenation index (OI) on day 1 has been shown to predict outcome[15]. This same group and others also suggest mean OI on day 1 is even more strongly predictive of outcome [16,17]. Another group used a simplified formula of [PaO2-PaCO2] from blood gas in the period after birth to predict need for Extracorporeal membrane oxygenation (ECMO) or death[18].

Although careful management of ventilation and PaCO2 are important to outcome, barotrauma can worsen outcome. Minimal ventilation and permissive hypercapnea [19] reduces complications like pneumothorax (pneumothorax is strongly associated with a lethal outcome[20]). The aim is to keep peak inspiratory pressures on conventional ventilation below 25 cmH2O pressure (maximum 30) [21]. The limits of permissive hypercapnea recommended by the CDH EURO Consortium is between 50 and 70 mm Hg; and pH ≥7.2[22]. Preductal O2 saturation is usually kept around 90% (±5%); postductal O2 saturation is correlated with other measures systemic oxygen delivery. Inotropes are used to increase systemic perfusion if needed. Adopting permissive hypercapnea and minimal ventilation strategies have allowed a moderate improvement in outcome [23] and even decrease the need for 'rescue ECMO' [24]. Therefore, like less aggressive timing of surgery in CDH, less aggressive ventilation has improved outcome for CDH in the modern era. High-frequency oscillatory ventilation (HFOV) offers an alternative ventilatory support for those with PPHN who fail on conventional ventilation, while minimising barotrauma to the lungs. Minimal ventilation pressures to reduce barotrauma in HFOV are in the range from 12 to 15 cm H2O[21]. One recent multi-centred randomised controlled trial demonstrated no advantage of initial HFOV versus conventional ventilation in CDH, but confirmed the rationale of initially using conventional ventilation as the initiating modality[12]. A previous Cochrane review of randomized controlled trials of HFOV versus conventional ventilation in term babies with PPHN found no evidence supporting the case for routine or rescue use of HFOV[25]. A randomised controlled cross over trial (excluding infants with CDH) of HFOV versus conventional ventilation and inhaled nitric oxide (iNO) concluded that the most effective treatment of PPHN was the combination of the iNO and HFOV [26]. No randomised trial exists investigating benefit in CDH. However HFOV is often used with clinical benefit alongside the other management strategies for PPHN, including iNO and cardiovascular support.

The management of the cardiac dysfunction and PPHN requires a multi-disciplinary approach between the neonatologist and cardiologist. Ensuring good oxygenation is the first step. The institution of effective gentle ventilation, either by conventional or then HFOV, is crucial. Systemic arterial pressure is maintained at acceptable levels with a combination of fluid administration and/or inotropic support as guided by echocardiography. iNO (5 to 20 parts per million) improves oxygenation and can reduce the acute need for ECMO and temporize while other modalities are instituted. iNO reduces requirement for ECMO in newborns with PPHN, but not in CDH[27]. The response to iNO should be confirmed using echocardiography. There have been no conclusive evidence that iNO reduced the need for ECMO or death in CDH, but individual response are seen.

In patients who are non-responsive to iNO or have rebound PPHN, oral or intravenous Sildenafil is considered. Sildenafil infusion enhances iNO mediated vasodilatation and has been shown to be associated with improved oxygenation in CDH[28] and improved outcome[29]. Its use is sanctioned by the CDH EURO Consortium[22]. Other vasodilators (milrinone and prostaglandins) can be considered depending on clinical course.

ECMO is reserved for patients with severe pulmonary or cardiac compromise refractory to other modalities. Indications for referral for consideration of ECMO commonly used include an OI > 40; rising lactates despite maximum ventilation and treatment for PPHN and inotropic support; and associated severe hypoxaemia and hypercapnea[21]. A Cochrane review into the RCTs investigating the benefits of ECMO in neonates concluded that the benefit of ECMO for babies with CDH is unclear[30]. However ECMO may have its uses in those that have reversibility of their respiratory disease. [31,32], and has shown occasional benefit in some patients[33]. Although one study did not identify any significant overall increased survival rate in recent era[32], introduction of ECMO was associated an increase in survival rate by post-hoc analysis. One issue may be that of careful selection.

Timing of surgery

Less aggressive timing of surgical intervention, allowing stablisation of the neonate, and more semi-elective surgery is now the norm. Even in the most stable of neonates, 24 to 48 hours of observation allows any cardiovascular instability and PPHN to declare itself However significantly delayed surgery is not without its problems, as surgical complications like obstruction, strangulation and volvulus can arise if surgical management is not instituted timely[34]. In another study, delaying surgery (unadjusted for severity of disease) was associated with increased mortality[35], but this relationship disappeared when adjusted for severity. Recently it was also shown that early repair of left liver-up CDH before ECMO can result in improved survival[36]. They used multivariate models to assess risk for ECMO at 1 hour of life and then found that 95% repaired in the first 60 hours and before ECMO survived; whereas 13 of 20 (65%) who had repair delayed and arrived to ECMO unrepaired survived. This was a retrospective analysis however. Two randomise studies of early versus late repairs performed in the 1990's did not demonstrate any statistically significant advantage to either immediate or delayed surgery[37,38].

No overarching clear cut indication of the best timing of surgery exist, other than the achievement of stability, without either major deterioration or improvement over a period of time. Serial OI as well as other cardiorespiratoy parameters (blood pressure, ductal shunting, urine output and lactate levels) can be used to indicate stability[39]. This delayed surgery after a period of stabilisation seems prudent, if not evidenced based at present. The best use of resources, reduction of the physiological stress of surgery during severe physiological instability and severe PPHN, and an approach of 'self-selection' seems to favor the approach of delayed surgery. At the same time recognising the window of opportunity for surgical intervention when a plateau in stability is achieved is also needed.

Patients with severe disease may be on ECMO many weeks[40], but outcomes in these patients can still be good. Some suggest that early repair on ECMO was associated with decreased length of time on ECMO, decreased complications, and a trend towards improved survival[31]. Another study, while not condoning repair on ECMO, identified an increased survival rate if repair could be delayed until off ECMO[41]. Therefore the optimal timing of surgery for patients on ECMO is difficult to definitively establish, but should include in these complex and logistic factors influencing the final outcome.

Thoracoscopic vs open surgery

Surgical management of CDH can be via a conventional open or a minimally invasive surgery (MIS) approach via laparoscopy or thoracoscopy. In recent years there has been increasing use of MIS in paediatric and neonatal surgery, including the management of CDH. There may be disadvantages though. CO2 is absorbed from the chest[42,43], which can lead to significant metabolic and physiological changes. The pathophysiological effects of intraoperative capnothorax are complex. Permissive hypercapnia is a mainstay of ventilatory management in the neonatal management of CDH and reduces morbidity. The limits of intraoperative ‘permissive hypercapnia’ in CDH have not been established. HFOV may offer a means of management of intraoperative gas exchange in CDH, with a few studies reporting on good outcome[44].

Few studies address intraoperative hypercapnia and oxygenation in detail. Some found no difference in maximum CO2 levels between approaches[45]. Other studies demonstrated differences in pH, but with little physiological effect. Most studies have however confirm a significant intraoperative increase in CO2 excretionand/or acidosis during thoracoscopic CDH repair[46]. One randomised controlled pilot study in 10 neonates demonstrated a significant intraoperative hypercapnia and acidosis in the thoracoscopic patients [47]. There are also concerns about the systemic effect of hypercapnia and on cerebral perfusion. One study showed a significant decrease in cerebral oxygenation during (from 87% to 75%) and after thoracoscopic CDH and oesophageal atresia repair[43], although the clinical effects of this is not known. It is also not known if the effect is directly related to systemic CO2 levels. This needs further research.

One other concern about thoracoscopic repair of CDH is quoted higher recurrence rate[46]. The Congenital Diaphragmatic Hernia Study Group[48] reported on 4,390 infants limited to recurrence during initial hospitalization. Of 151 MIS repairs 12 recurred (7.9%) compared to 114 for open (2.7%), with a significant increased odds for recurrence (OR 3.59, 95% CI:1.92 – 6.71). The use of a patch significantly increased the recurrence rate. MIS repairs that used a patch had the highest recurrence rate at 8.8%. However there was a significant increased odds of survival for infants undergoing MIS repairs (OR 5.57; 95% CI: 1.34 – 23.14). This may represent selection bias however. One systemic review of 3 eligible published series concluded that there is a higher incidence of recurrence with MIS (OR 3.2) but a non-significant trend to lower incidence of death (OR 0.33)[49].

Not all report a higher recurrence rate however[50]. Comparable recurrence rates (as low as 3.6%) are reported. Open repair is associated with a higher incidence of abdominal complications like intestinal obstruction[51]. Maybe selection criteria, including anatomical (stomach in the abdomen) and physiological (minimal ventilator support; peak inspiratory pressures in the low 20s), may allow safe MIS approach in CDH. OI (>3.0) has been shown as the only selection criteria significantly predictive of postoperative complications for thoracoscopic approach [52].

As part of the VICI trial on HFOV versus conventional ventilation, preoperative and postoperative cerebral and renal oxygen saturation using near infra-red specteroscopy was measured[53]. There was a modest drop in both values intraoperatively. An open approach was used in all their patients. There was a modest but statistically significantly lower levels in the HFOV arm, that was thought to be due to differences in venous return between modalities. While further studies are awaited on which further guidelines can be developed, careful selection in those experienced in MIS[52], anaesthetic vigilance, monitoring and surveillance [43,46], and follow up of these cases are required. Prospective, controlled and randomised studies on the outcome of MIS repair is needed to inform further practice.

Postoperative follow up and lung function

There are many multi-system and multi-disciplinary issues in CDH patients that continue from the postoperative period into the long-term. Surgical follow up with a high index of suspicion for signs and symptoms of recurrence will allow prompt investigation, diagnosis and management of this and other surgical complications[54]. Chronic lung disease and other respiratory issues affect many patients. Although alveolar growth continues up to 8 years of age, and children can outgrow any mild respiratory compromise[55], chronic respiratory problems in severe CDH persists[56], and include increased lower respiratory tract infections, reactive airway disease and restrictions in lung function. Pulmonary hypertension which persists into infancy and childhood is associated with poorer outcome[57]. There is a late mortality, due to chronic lung disease and associated or secondary cardiac dysfunction, up to 4 years of age[58]. Significant disturbances in ventilation and lung perfusion persists into childhood and adolescence [59,60].

Gastro-oesophageal reflux, feeding issues and poor growth are long-term gastrointestinal/nutritional issues. Failure to thrive (FTT) in CDH survivors can result from and imbalance between calorific need and nutritional input; with metabolic demands increasing the former and gastrointestinal complications limiting the latter. Children with CDH have elevated resting energy expenditure(REE), not just in the short term as a known response to stress and surgery[61], but also in the long-term [62], and many patients are hypermetabolic. REE is the greatest component of total energy expenditure (Fig. 1). This increased REE therefore necessitates an increased calorific intake, as their TEE is also therefore elevated. The cause of the increase REE in CDH survivors is not known as far as we are aware, but can include the increased work of breathing, increased cardiac workload in those with heart disease, and increased need to fight infections. Not meeting TEE with calorific needs results in a shift of the energy requirement for growth[63] to these demands, resulting in FTT.

Figure 1. Components of total energy expenditure (TEE) in children. Numbers represent percentages of each component to TEE. REE = resting energy expenditure. DIT = diet induced thermogenesis; which is thought to contribute 5-10%, but is represented by 5 for simplicity.

10.3-1.1

Other patients may not be hypermetabolic but have gastrointestinal complications which limit their ability to intake sufficient calories. Gastro-oesophageal reflux disease is prevalent in CDH survivors[64]. Feeding issues without significant reflux also exist[65]. Occasionally these feeding issues need medical and/or surgical management (oral supplemental feeding, feeding tubes/gastrostomies, fundoplication) to improve nutritional status or quality of life. Surgical complications of intestinal adhesions and recurrent herniation can occur and should be ruled out in those with gastrointestinal symptoms.

Neurodevelopmental delay and hearing loss are nonsurgical complications, which are consequences of poor oxygenation[66,67], and can be worse in children who receive ECMO support[58]. Other predictors of poor neurodevelopmental outcome are right sided CDH, liver up, need for patch and chronic lung disease. These surgical, nutritional, cardiac, respiratory, neurodevelopmental and neurofunctional outcomes in children with CDH have encouraged the need for multi-disciplinary follow up to both identify and manage these[68]. These wide ranging systemic morbidities which can be affect the CDH patient in the long term, need a variety of specialities involvement, but with inter-specialty correlation in the overall care. Multi-disciplinary follow up is required. This can take the form of visits to the different specialities involved in an individualised manner. But those requirements may also be best served by a multi-disciplinary one-stop clinic. This latter multidisciplinary one-stop clinic follow-up is becoming the gold-standard for postoperative follow up.

Conclusion

Multi-disciplinary input is needed in children with CDH from antenatal care through to the long-term outpatient follow up. Antenatal US can be used to help prognosticate postoperative outcome if uniformity in measuring and reporting are used. The use of observed to expected antenatal measurements is preferred as they give more specific and accurate information, with MRI seeming to have a specific role in confirming prognostication in those thinking of antenatal intervention. Conventional ventilation with minimal ventilation and permissive hypercapnea improve outcome. Step-wise use of HFOV, iNO and Sildenafil alongside cardiovascular support can preclude ECMO, which is useful in selected cases. Multi-disciplinary follow up is required, and may a multi-disciplinary one-stop clinic may become more common and a gold standard.  


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Figure 1. Components of total energy expenditure (TEE) in children. Numbers represent percentages of each component to TEE. REE = resting energy expenditure. DIT = diet induced thermogenesis; which is thought to contribute 5-10%, but is represented by 5 for simplicity.