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Neonatal pneumothorax in congenital diaphragmatic hernia: Be wary of high ventilatory pressures

Background Patients with congenital diaphragmatic hernia (CDH) require invasive respiratory support and higher ventilator pressures may be associated with barotrauma. We sought to evaluate the risk factors associated with pneumothorax in CDH neonates prior to repair. Methods We retrospectively reviewed newborns born with CDH between 2014 and 2019 who developed a pneumothorax, and we matched these cases to patients with CDH without pneumothorax. Results Twenty-six patients were included (n=13 per group). The pneumothorax group required extracorporeal life support (ECLS) more frequently (85% vs 54%, p=0.04), particularly among type A/B defects (31% vs 7%, p=0.01). The pneumothorax group had higher positive end-expiratory pressure (PEEP) within 1 hour of birth (p=0.02), at pneumothorax diagnosis (p=0.003), and at ECLS (p=0.02). The pneumothorax group had a higher mean airway pressure (Paw) at birth (p=0.01), within 1 hour of birth (p=0.01), and at pneumothorax diagnosis (p=0.04). Using multiple logistic regression with cluster robust SEs, higher Paw (OR 2.2, 95% CI 1.08 to 3.72, p=0.03) and PEEP (OR 1.8, 95% CI 1.15 to 3.14, p=0.007) were associated with an increased risk of developing pneumothorax. There was no difference in survival (p=0.09). Conclusions Development of a pneumothorax in CDH neonates is independently associated with higher Paw and higher PEEP. A pneumothorax increases the likelihood of treated with ECLS, even with smaller defect.


INTRODUCTION
Congenital diaphragmatic hernia (CDH) is a complex condition occurring in 1 in 3000 live births. 1 Severe pulmonary hypoplasia and persistent pulmonary hypertension are major contributors to mortality and longterm morbidity. Advances in neonatal care including standardized protocols for gentle ventilation and permissive hypercapnia; application of rescue modalities, such as highfrequency jet ventilation (HFJV) and highfrequency oscillatory ventilation (HFOV); and utilization of extracorporeal life support (ECLS) have been tried to improve outcomes. [2][3][4][5] Despite these interventions, there remains a high risk of morbidity and mortality in neonates with CDH. 6 7 Gentle ventilation and lung-protective approaches have been described as strategies to limit the barotrauma to the hypoplastic lungs of patients with CDH. [8][9][10] Low positive end-expiratory pressure (PEEP) helps to prevent overdistention of the lung and facilitates improved lung compliance and decreased pulmonary vascular resistance. 11 12 Other studies have looked at the use of HFJV as an effective means of delivering adequate ventilation and oxygenation in infants exhibiting hypercarbia and hemodynamic instability on conventional mechanical ventilation (CMV). 13 HFJV uses small, highvelocity breaths delivered through a valve into

Key messages
What is already known on this topic ⇒ The concept of gentle ventilation has been used to improve outcomes in congenital diaphragmatic hernia. ⇒ Despite the use of gentle ventilation, there remains a 10%-23% rate of pneumothorax. ⇒ There is an increased risk of mortality when a pneumothorax develops preoperatively.
What this study adds ⇒ Elevated mean airway pressures and peak inspiratory pressures are risk factors for developing pneumothorax. ⇒ Development of pneumothorax is associated with increased use of extracorporeal life support. ⇒ Children with type A and B defects who develop a pneumothorax are more likely to use extracorporeal life support.
How this study might affect research, practice or policy ⇒ As high-frequency modes of ventilation become more frequently used in children with congenital diaphragmatic hernia, guidelines that address these ventilatory settings will be important to avoid pneumothorax while continuing to improve outcomes.
Open access the breathing circuit while coupled to a conventional ventilator to deliver PEEP, thereby allowing for optimal lung expansion while mitigating the risk of lung injury by avoiding high tidal volumes. 2 13 14 Despite varying protocols using gentle ventilation, patients with CDH develop pneumothorax at an alarming rate (10.5%-23%) with an increased risk of mortality. [15][16][17] Risk factors contributing to the development of preoperative pneumothorax in CDH are not clear. Recent studies have found large diaphragmatic defects and higher mean airway pressures have been associated with developing a pneumothorax. The purpose of the study was to determine the institutional incidence and risk factors contributing to developing a pneumothorax in neonates with prenatally diagnosed CDH. We hypothesize that a higher mean airway pressure (Paw) is associated with increased risk of pneumothorax.

Patient population
All patients with prenatally diagnosed CDH born between June 2014 and December 2019 were identified. Newborns who received either CMV or HFJV and developed a pneumothorax before surgical repair were selected for study. Pneumothorax was diagnosed based on the radiology reports abstracted from the patients' electronic medical records.
Owing to the small number of patients and the inability to compare ventilator pressure measurements, newborns who received HFOV were excluded. Cases were matched (1:1) with a patient with CDH who did not develop a pneumothorax prior to surgical repair (control) by gestational age, laterality of defect (left sided), liver position, and CDH study group defect type (A through D). 18 To prevent potential bias based on changes in management strategies over time, cases were matched with controls who were born no more than 4 months apart. Patients with postnatally diagnosed CDH were not included given the potential variability in postnatal care that could have impacted the development of pneumothorax.

Demographics
During the study period, 79 newborns had an antenatally diagnosed CDH of which 15 (16%) developed a pneumothorax prior to surgical repair (figure 1). Two patients were excluded because they received HFOV prior to developing a pneumothorax. The 13 cases that met the inclusion criteria were then matched with 13 control patients who did not develop a pneumothorax. There were no differences in prenatal factors including o/e LHR (p=0.33), o/e TLV (p=0.45), gestational age (p=1.00), or side of the CDH defect (p>0.99) (table 1). Diagnosis of pneumothorax occurred at a median of 110 min (IQR 66, 180) following birth. The pneumothorax was ipsilateral to the CDH defect in 31% (4/13), contralateral to the defect in 31% (4/13), and bilateral in 38% (5/13). Overall, the pneumothorax group was treated more frequently with nitric oxide (100% vs 38%, p=0.001) and ECLS (85% vs 46%, p=0.04) (table 1). Median time from birth to ECLS was similar between the pneumothorax group and the control group [7 hours (2-13) vs 9 hours (9-9), p=1.00]. Among the subgroup of less severe patients with a type A/B defect, those who developed a pneumothorax were more likely to require ECLS (31% vs 7%, p=0.01) and nitric oxide (31% vs 7%, p=0.01) (table 2). There was no difference in duration of ventilation (p=0.08) or survival among this subgroup of type A/B defects who developed a pneumothorax versus those who did not (75% vs 100%, p=0.26).

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Ventilation data HFJV was more common among cases at the time of pneumothorax (77% vs 31%, p=0.03) (  After matching for defect type, liver position, gestational age within a 4-month time period, our final study population was 26 patients. HFOV, high-frequency oscillatory ventilation.

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Outcome Overall survival to discharge was 65% (16/26) with no difference in survival between the pneumothorax group and the control group (p=0.09) (table 1). There was no difference in duration of ECLS (p=0.67), duration of mechanical ventilation (p=0.64), or the proportion who were discharged on home oxygen (p=0.42) (table 1).

DISCUSSION
The purpose of our study was to determine our institutional incidence and risk factors contributing to developing a pneumothorax in neonates with prenatally diagnosed CDH. Pneumothorax occurred in 16% of our patients, which is consistent with previous literature. 16 17 Among newborns with CDH, we found that higher PEEP and Paw settings were associated with the development of a pneumothorax after controlling for gestational age, CDH defect size, and liver position. In addition, we found that pneumothorax was associated with being treated with ECLS prior to surgical repair, most notably in those with smaller defect sizes (A or B defect).
As operative management of CDH has evolved during the last several decades, so have the resuscitative efforts immediately following birth. Past hyperventilation strategies have been shown to damage the already hypoplastic lungs of patients with CDH, further delaying adequate oxygenation and contributing to subsequent ventilatorinduced lung injury (VILI). 20 Given that lung oxygenation is a crucial factor in decreasing pulmonary vascular resistance and in improving pulmonary blood flow Open access with benefits to both survival and long-term outcomes, ventilator management strategies play a critical role in the survival of a patient with CDH. 8 12 14 As such, there has been a transition during the past 30 years towards favoring and standardizing the concept of gentle ventilation. 21 By allowing permissive hypercapnia, lower pH, lower levels of oxygen, lower ventilator pressures and decreasing the use of neuromuscular blockers and sedatives, gentle ventilation attempts to reduce the risk of barotrauma and VILI. 5 Even in the era of gentle ventilation, 10.5%-23% of newborns with CDH will develop a pneumothorax. 10 15 17 In our population, pneumothoraces occurred 53% of the time on the ipsilateral side of the CDH defect, suggesting both sides are at risk. In comparison, the literature reports a 62%-100% rate of developing an ipsilateral pneumothorax. 16 17 By combining the ventilation data from the patients on CMV and HFJV, we found significant differences in both PIP and PEEP at multiple time intervals. Theoretically, the PIP delivered by CMV may not be equivalent to the PIP generated by HFJV. 14 Given the difference between the two modes of ventilation, combining PIP data from CMV and HFJV may lead to bias. For this reason, we performed a subgroup analysis for CMV settings and another for HFJV settings. In the subgroup analysis, PEEP levels generated by CMV were higher in the pneumothorax group at pneumothorax and at ECLS. HFJV PIP was only significantly higher in the pneumothorax group at birth. We suspect that this may reflect a type II error based on small sample size.
We attempted to identify the perinatal risk factors associated with the development of pneumothorax. After controlling for gestational age, left-sided defect, CDH defect size, and liver position, our multiple logistic regression found increased PEEP and Paw were associated with the development of a pneumothorax. Guevorkian et al 22 23 24 Regarding Paw, in a multi-institutional study of 495 neonates with CDH of whom 52 developed a pneumothorax, Masahata et al 16 found higher Paw was associated with developing a pneumothorax with an OR of 1.172 (95% CI 1.022 to 1.345), which is consistent with previous literature. 25 With the findings of our study, we conclude PEEP greater than 5 cmH 2 O and Paw greater than 13 cmH 2 O at any time should be avoided to limit the risk of pneumothorax. We acknowledge the PEEP in both groups is higher than these recommendations and is due to the local practice of teams managing our patients with CDH. We have modified our institutional protocols to reflect these recommendations.
While other studies have shown ECLS is more frequently applied in patients with pneumothorax, the higher frequency of patients with smaller defects (types A and B) on ECLS in the pneumothorax group compared with the control group is concerning. 16 With a similar max pCO 2 following delivery and time to ECLS from birth, patients with smaller defects who developed pneumothorax did not initially appear to be clinically worse than the control group. We were unable to show a mortality difference between the two groups which may be due to the sample size. However, Masahata et al 16 showed a lower rate of survival in those who developed a pneumothorax compared with those without.
Our study has several limitations. This single institution study is retrospective and may not be generalizable to a broader CDH population. The data available from chart review lacked specific details required to analyze the pressures used during the initial resuscitation and stabilization immediately after birth while patients were being ventilated with a manual T-piece resuscitator, which can be set to not exceed a specific pressure. Given the limited sample size, we also were unable to identify a difference in survival or whether receiving HFJV increased the odds of developing a pneumothorax. Regarding the variability in ventilator modes and settings found in our study,  In conclusion, development of pneumothorax in CDH prior to surgical repair is independently associated with higher PEEP and Paw levels at multiple time intervals. Furthermore, developing a pneumothorax was found to increase the likelihood of receiving ECLS, particularly for less severe defect types. While continuing gentle ventilation protocols to minimize variability of care, additional research is needed to fully understand the risk factors that contribute to the development of pneumothorax in CDH during the preoperative neonatal period in hopes of increasing case management and survival outcomes for patients with CDH.

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Contributors NR made substantial contributions to the conception or design of the work, to the acquisition of data, to the analysis of data, and to the interpretation of data for the work. GAN made substantial contributions to the acquisition of data. AGK made substantial contributions to the conception or design of the work, and to the acquisition of data. NM made substantial contributions to the analysis of data, and to the interpretation of data for the work. EEP is the guarantor of the study, made substantial contributions to the conception or design of the work, to the acquisition of data, analysis of data, and to the interpretation of data for the   work. All the authors helped draft the work and revised it critically for important intellectual content; approved the final version to be published; and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The Medical School Institutional Review Board (IRBMED) reviewed and approved this study (HUM00007285).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement No data are available. Not applicable.
Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.