Congenital diaphragmatic hernia (CDH) affects 1 in 2500-3000 live births [1].The management of a neonate with CDH is challenging. Despite improvement of health care, mortality still exceeds 30% and morbidity among survivors is high. Overall survival is highly variable; varying from 70-80% in developed countries [1-4] and 38-72% in low- and middle-income countries [5-10].

Delivery room management included involvement of at least two skilled personnel, elective intubation, and the use of T-piece resuscitator for positive pressure venti-lation. Postnatal ventilatory management in the NICU utilized lung-protective strategy with conventional venti-lation with time-cycled, pressure-limited ventilation (Web Fig. 1). Inspired oxygen concentration (FiO2) was adjusted to target pre-ductal oxygen saturation of >85%. Permissive hypercapnia (PaCO2 55-65 mmHg) was tolerated as long as pH was ³7.25. If hypercapnia persisted on conventional ventilation or when PIP required to target the desired PaCO2 levels exceeded 20-25 cm H20, neonates were switched to high frequency oscillatory ventilation (HFO). Persistent pulmonary hypertension was clinically suspected when there was labile oxygen saturation (SaO2), pre-ductal SaO2 <85% despite high FiO2 or pre-post ductal difference in oxygen saturation of >10%. Echocardiography was performed in all cases to confirm PPHN, evaluate myocardial function and to rule out cardiac malformation. We used inhaled nitric oxide (iNO) in a few cases as a bridge to surgery or prior to considering the use of extracorporeal membrane oxygenation (ECMO). ECMO was used in two cases due to the presence of significant hypoxia (oxygenation index >40) and/or persistent hypotension/acidosis despite optimal ventilation and management of pulmonary hypertension. The management protocol, including supportive therapy, have been outlined in Web Fig.1.

Surgical repair was done when the neonate was clinically stable for at least 24 hours. Clinical stability was defined as ventilatory parameters of FiO2 requirement of <60%, MAP <12, PaO2 >50 mm Hg, normal blood pressures with minimum inotropic support (dopamine and/or dobutamine of £10 µg/kg/min) and urine output >0.5 mL/kg/hr). Repair was either primary or patch repair based on the size of the defect.

TABLE I	Demographic Characteristics, Resuscitation Details and Postnatal Course (N=37)

All cases requiring ventilatory support were initiated on conventional ventilation and about a half (n=14) were put on high frequency mode (HFO) subsequently. The median (IQR) initial and maximum peak inspiratory pressures in conventional mode were 17 (15-20) and 19 (15-21) cm H2O, respectively. Median oxygenation index (OI) when HFO was initiated was 21 (14-45.75). Pneumothorax was noted in 11 (30%: 6 cases before and rest secondary to surgery) cases and PPHN in 19 (51%) cases: out of which 7 were stabilised and operated. In 13 neonates (35%) with refractory PPHN, inhaled nitric oxide was used at a median age of 2 (0.25-7) days. Pulmonary vasodilator medications like sildenafil and milrinone were used in approximately one-third. The median duration of ventilation among survivors was 12 (5.8-15) days.

Surgical repair could be performed only in 18 neonates: in 14 cases at median age of 2 days (IQR 1-5.7), while in rest at or beyond 2nd week. Closure of diaphragmatic defect was primary in 14 (78%) neonates while a patch was used in the rest (n=4). Extracorporeal membrane oxygenation (ECMO) support was used in two cases on day 14 and 17, respectively during primary repair: both cases succumbed due to multi-organ dysfunction. One case of left sided CDH, with persistent ventilatory requirement and repeated extubation failure after surgical repair improved after repair of a diaphragmatic hernia on the contralateral side, detected later.

TABLE II	Significant Predictors of Mortality Among Babies with Congenital Diaphragmatic Hernia (N=37)

In our cohort overall mortality was 59.5%; 51% (19/37) died before surgical correction and 8% (3/37) died post-operatively. Univariate analysis was carried out for sex, laterality of lesion, co-morbid malformations intubation in delivery room, chest compression in delivery room, fluid bolus, APGAR scores, cord pH, initial PIP, need for HFO, age at surgery, duration of hospital stay, PPHN, shock, sildenafil use, milrinone use, inhaled NO use, use of antibiotics, sepsis, and use of patch for closure (Table II). The following factors were associated with increased mortality: low 1 and 5 minute Apgar scores, higher initial PIP requirement on conventional ventilation, associated congenital malformations and PPHN. Requirement of a patch repair was associated with an increased risk for mortality relative to primary repair (100% vs. 6.67%, P = 0.005). On multivariate analysis using generalized linear model with mortality as dependent variable and factors that were considered to be clinically important (gestation, birth weight, malformation, Apgar score at 5 min and PPHN) as independent variables; only PPHN was associated with a higher mortality with adjusted risk ratio of 3.74 (95% CI 1.45-9.68) (Table III).

TABLE III	Multivariate Analysis for Predictors of Mortality (N=37)

The overall mortality among CDH cases born in our centre was 59% and the presence of PPHN was a significant predictor. We followed a protocol based management with lung protective ventilation, permissive hypercapnia, and elective surgical repair. There is paucity of reports from the LMICs regarding the outcomes of CDH patients [5-10].

The differences in survival when compared to the developed world can be attributed to factors like lack of a dedicated CDH team, absence of any hidden mortality in current cohort (ours was an unselected population of all inborn neonates). In general, population-based studies have reported lower survival than studies from single institution; this difference being due to the presence of a ‘hidden’ mortality [12,13]. Skari, et al. [14] noted that prenatal diagnosis of CDH, associated major malformations, side of hernia and study population had a major influence on mortality. Therefore, these factors should be taken into consideration while interpreting survival outcomes from various studies. Ours was an unselected population which included all in-born neonates irrespective of associated malformation and laterality.

Only few studies have reported postnatal risk factors for poor outcomes in CDH neonates in LMICs [5–8,10]; most of them are from outborn and from referral units, thus leading to a selection bias. The poor prognostic factors include established antenatal diagnosis, intramural birth, and presence of an associated malformation, PPHN and absence of a hernia sac in intraoperative findings. PPHN was the most important determinant of survival in our study similar to previous studies [6,15,16].

We used ECMO in two cases as a bridge to surgical repair. Low utilisation of ECMO has been reported even from large surgical centres in Europe [17]. The centres following preoperative medical stabilization with selective use of ECMO followed by surgical repair have reported higher survival [3,13,18], when compared with facilities not using ECMO [19,20].

In this cohort, we screened for associated malformations using echocardiography, ultrasonography, karyotyping (in neonates with suspected syndrome on clinical evaluation) and autopsy (whenever parents consented). However, the outcomes reported from a limited study population and from a single center are limitations of this study. We did not have antenatal data pertaining to severity of CDH in many cases, due to late referral. Ours being a tertiary care centre, there could be a referral bias due to referral of complicated or severe cases diagnosed antenatally.

Management of CDH in developing world is still challenging. Our centre had a high mortality rate despite good neonatal intensive care and surgical management. PPHN was an important predictor of mortality.