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## **Meet the editors**

Dr. Hany Aly is a professor in Pediatrics and Obstetrics at the George Washington University and Children's National Medical Center. He is the director of the Division of Newborn Services at the George Washington University Medical Center in Washington, DC, USA, and the editor-in-chief for *Journal of Neonatal-Perinatal Medicine*. He is a regional trainer for the Neonatal Re-

suscitation and a member of the American Academy of Pediatrics, American Pediatric Society, and Society of Pediatric Research.

Dr. Hesham Abdel-hady is a professor in Pediatric/Neonatology and Chief of the Division of Neonatology at Mansoura University Children's Hospital in Egypt. He is a regional trainer for the Neonatal Resuscitation Program of the American Academy of Pediatrics, a board member of the International Society for Evidence-Based Neonatology (EBNEO), a member of the Society of

Pediatric Research, and an editorial board member for multiple international journals.

## Contents

#### **Preface XI**

#### Chapter 9 **Non‐Pulmonary Management of Newborns with Respiratory Distress 139** Petja Fister and Štefan Grosek

## Preface

Chapter 9 **Non‐Pulmonary Management of Newborns with Respiratory**

**Distress 139**

**VI** Contents

Petja Fister and Štefan Grosek

Respiratory management of the newborn is a broad field in which we are convinced it is hard to be efficiently covered in a single book; therefore, we did not intend to cover the basic knowledge and the day-to-day routine management of infants with respiratory distress. Readers can easily find such information in various sources. The scope of this book is to focus on a few specific areas of respiratory management that are often challenging. For ex‐ ample, it covers ventilator management of infants with unusually severe bronchopulmonary dysplasia and infants with omphalocele. The book also provides an overview on new trends in the management of fetal and transitioning lungs in infants delivered prematurely, posi‐ tioning of endotracheal tube in extremely low birth weight infants, noninvasive respiratory support, and utilization of a strategy stems on protocol-driven respiratory management.

Neonatal resuscitation is a cornerstone skill for healthcare providers in the field of neonatol‐ ogy. The interest to ensure efficacious resuscitation and to monitor physiologic parameters of neonates during chest compression cannot be overemphasized. This book includes a chapter on noninvasive respiratory function monitoring during chest compression analyz‐ ing the efficacy and quality of chest compression and exhaled carbon dioxide.

Lastly, the relationship between ventilator-related lung injury and brain development is an area of recent interest; we like to use the term "lung-brain axis," and we believe there is a wealth of knowledge yet to be discovered in this area of management. This book includes a chapter on neonatal encephalopathy treated with hypothermia along with mechanical venti‐ lation. The interaction of cooling with respiration and the strategies to optimize oxygenation and ventilation in asphyxiated newborns are discussed. This book brings new information in a simplified structure that allows readers to enjoy as they learn. We thank contributing authors for their valuable time and expertise that made this book possible.

> **Hany Aly, MD, FAAP** The George Washington University and the Children's National Medical Center Washington, DC, USA

> > **Hesham Abdel-Hady, MD** Mansoura University Children's Hospital Mansoura, Egypt

## **Respiratory Function During Chest Compressions**

Georg M Schmölzer, Anne Solevåg, Erica McGinn, Megan O'Reilly and Po-Yin Cheung

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/63510

#### **Abstract**

Chest compression (CC) is an infrequent event (0.08%) in newborns delivered at nearterm and term gestation, and occurs at a higher frequency (10%) in preterm deliver‐ ies. In addition, outcome studies of deliveries requiring resuscitation or chest compression have reported high rates of mortality and neurodevelopmental impair‐ ment in surviving children. A respiratory function monitor (RFM) can help guide a resuscitator during cardiopulmonary resuscitation (CPR) in a neonate and help assess the quality and efficacy of chest compression. Utilizing a non-invasive respiratory function monitor during chest compression may decrease high mortality rates in addition to having many distinct advantages, which will benefit both the newborn and the resuscitators. There are several different ways that a respiratory function monitor can assist a resuscitator during chest compression; these include confirming and ensuring adequate lung ventilation, analyzing the efficacy and quality of chest compression and exhaled CO2 monitoring.

**Keywords:** infants, newborn, delivery room, neonatal resuscitation, chest compres‐ sion

## **1. Introduction**

Fortunately, the need for chest compression (CC) or medications in the delivery room is rare. Only about 0.1% of term infants receive these interventions, resulting in approximately 1 million newborn deaths annually worldwide. In addition, chest compression or medications is more frequent in the preterm population (~15%) due to birth asphyxia [1, 2]. Fortunately, the majority

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

of newborn infants successfully make the transition from fetal to neonatal life without any help [3]. An estimated 10% of newborns need help to establish effective ventilation (e.g., positive pressure ventilation, PPV), which remains the most critical step of neonatal resuscitation [3]. However, clinicians struggle to deliver an adequate tidal volume (*V*T) [4]. In addition, mask positive pressure ventilation is often impaired by either mask leak or airway obstruction [5]. Manikin studies have further demonstrated thatinitiation of chest compression increases mask leak and therefore impedes effective ventilation [6, 7]. It is imperative to give optimal ventila‐ tionduringchest compressiontomaximize efficacy[8].Recently, a respiratoryfunctionmonitor (RFM) has been described to be support the clinical team during simulated [9, 10] and realtimeneonatalresuscitation[11–14].This chapterdiscusseshowanRFMcanaidduringneonatal resuscitation.

## **2. Respiratory function monitor**

#### **2.1. VT, gas flow, airway pressure, and exhaled CO2 monitor**

Gas flow, *V*T, airway pressure, and *exhaled* CO2 (ECO2) can be measured by any respiratory function monitor using a flow sensor placed between a ventilation device and facemask or endotracheal tube [11, 14]. Inspiratory and expiratory tidal volume passing through the sensor can be calculated by any flow sensor (e.g., fixed orifice pneumotach or a hot wire anemometer) by integrating the flow signal [11, 14]. Airway pressure is measured by directly connecting a line to the circuit, which displays peak inflation pressure and positive end expiratory pressure. Any respiratory function monitor continuously displays waves (e.g., pressure, flow, and tidal volume) and numerical values (e.g., airway pressure, tidal volume, and respiratory rate) [11, 14]. In addition, the percentage of mask leak or around a tracheal tube is calculated and displayed. ECO2 is measured using a non-dispersive infrared absorption technique. According to manufacturers, the accuracy for gas flow is ±0.125 L/min and for ECO2 is ±2 mmHg.

### **3. Mask leak**

Mask ventilation studies in the delivery room have reported variable mask leak during positive pressure ventilation [4], which can be significantly decreased if mask leak is displayed on an RFM [13]. Using a manikin, Binder-Heschl et al. reported that mask leak significantly increased from 15% during positive pressure ventilation to 32% after chest compression was started [6]. This is further supported by a study by Solevåg et al. who reported that tidal volume delivery is significantly decreased using continuous chest compression with non-synchronized ventilation compared to the current 3:1 cardiopulmonary resuscitation (CPR) [7]. However, when a resuscitation used an RFM to asses mask leak, it was significantly reduced [6]. Unfortunately, the data in newborn infants are sparse and limited to a case report by Li et al. [12]. During chest compression, mask leak was 100% and did not result in an increase in heart rate, suggesting that adequate tidal volume was not delivered (**Figure 1**) [12].

**Figure 1.** As CC is initiated in an extremely preterm infant, the traces indicate large mask leak. This results in ineffec‐ tive ventilation and no *V*T delivered, which could lead to failure of achieving ROSC.

## **4. Tidal volume**

of newborn infants successfully make the transition from fetal to neonatal life without any help [3]. An estimated 10% of newborns need help to establish effective ventilation (e.g., positive pressure ventilation, PPV), which remains the most critical step of neonatal resuscitation [3]. However, clinicians struggle to deliver an adequate tidal volume (*V*T) [4]. In addition, mask positive pressure ventilation is often impaired by either mask leak or airway obstruction [5]. Manikin studies have further demonstrated thatinitiation of chest compression increases mask leak and therefore impedes effective ventilation [6, 7]. It is imperative to give optimal ventila‐ tionduringchest compressiontomaximize efficacy[8].Recently, a respiratoryfunctionmonitor (RFM) has been described to be support the clinical team during simulated [9, 10] and realtimeneonatalresuscitation[11–14].This chapterdiscusseshowanRFMcanaidduringneonatal

Gas flow, *V*T, airway pressure, and *exhaled* CO2 (ECO2) can be measured by any respiratory function monitor using a flow sensor placed between a ventilation device and facemask or endotracheal tube [11, 14]. Inspiratory and expiratory tidal volume passing through the sensor can be calculated by any flow sensor (e.g., fixed orifice pneumotach or a hot wire anemometer) by integrating the flow signal [11, 14]. Airway pressure is measured by directly connecting a line to the circuit, which displays peak inflation pressure and positive end expiratory pressure. Any respiratory function monitor continuously displays waves (e.g., pressure, flow, and tidal volume) and numerical values (e.g., airway pressure, tidal volume, and respiratory rate) [11, 14]. In addition, the percentage of mask leak or around a tracheal tube is calculated and displayed. ECO2 is measured using a non-dispersive infrared absorption technique. According to manufacturers, the accuracy for gas flow is ±0.125 L/min and for ECO2 is ±2 mmHg.

Mask ventilation studies in the delivery room have reported variable mask leak during positive pressure ventilation [4], which can be significantly decreased if mask leak is displayed on an RFM [13]. Using a manikin, Binder-Heschl et al. reported that mask leak significantly increased from 15% during positive pressure ventilation to 32% after chest compression was started [6]. This is further supported by a study by Solevåg et al. who reported that tidal volume delivery is significantly decreased using continuous chest compression with non-synchronized ventilation compared to the current 3:1 cardiopulmonary resuscitation (CPR) [7]. However, when a resuscitation used an RFM to asses mask leak, it was significantly reduced [6]. Unfortunately, the data in newborn infants are sparse and limited to a case report by Li et al. [12]. During chest compression, mask leak was 100% and did not result in an increase in heart

rate, suggesting that adequate tidal volume was not delivered (**Figure 1**) [12].

resuscitation.

2 Respiratory Management of Newborns

**3. Mask leak**

**2. Respiratory function monitor**

**2.1. VT, gas flow, airway pressure, and exhaled CO2 monitor**

The purpose of inflations during chest compression is to deliver an adequate tidal volume to facilitate gas exchange [3]. A manikin study reported that tidal volume increases once chest compression was started compared to mask ventilation alone [7]. Interestingly, a further manikin study examined different auditory prompts during simulated neonatal cardiopulmonary resuscitation and reported higher tidal volumes in all groups compared to baseline [15]. These studies suggest a change in tidal volume once chest compressions are initiated. An increase or decrease in tidal volume could cause lung derecruitment, which could hamper oxygenation and therefore return of spontaneous circulation (ROSV) [12]. In a porcine model of neonatal resuscitation, Li et al. recently described that using the current recommendation of 3:1 chest compression to ventilation ratio (**Figure 2**) [3], lung derecruitment occurs [8]. The study further compared continuous chest compressions with asynchronous ventilations and found similar results [8], however, when chest compression superimposed by sustained inflation (CC + SI) (**Figure 3**) [16] improved tidal volume delivery and continuous lung recruitment was observed, potentially leading to better alveolar oxygen delivery and lung aeration.

**Figure 2.** *V*T (mL/kg) changes during 3:1 chest compression:ventilation ratio (3:1 C:V) (A), continuous chest compres‐ sions and asynchronous ventilations (CCaV) (B), and continuous chest compressions superimposed by sustained infla‐ tions (CC + SI) (C). #p < 0.05 exhaled CO2 (ECO2) compared with CC + SI [8] (with permission).

**Figure 3.** CC superimposed by sustained inflation; adequate lung ventilation and *V*T delivery are displayed: (i) ade‐ quate gas flow towards and away from the infant; (ii) average *V*T of 4 mL/kg is delivered without leak.

## **5. Exhaled carbon dioxide (ECO2)**

**Figure 2.** *V*T (mL/kg) changes during 3:1 chest compression:ventilation ratio (3:1 C:V) (A), continuous chest compres‐ sions and asynchronous ventilations (CCaV) (B), and continuous chest compressions superimposed by sustained infla‐

tions (CC + SI) (C). #p < 0.05 exhaled CO2 (ECO2) compared with CC + SI [8] (with permission).

4 Respiratory Management of Newborns

There is increasing evidence that continuous monitoring of exhaled carbon dioxide (ECO2) can predict rise of heart rate during neonatal transition [17], monitor lung aeration at birth [11, 18– 20], and predict return of spontaneous circulation during neonatal cardiopulmonary resuscitation (**Figure 4**) [21]. Blank et al. used a Pedi-Cap during mask positive pressure ventilation and reported a significant increase in heart rate once the Pedi-Cap turned yellow [17]. Similar results have been described in animal models and a further delivery room study [18]. During neonatal cardiopulmonary resuscitation ECO2 is a reliable parameter to examine return of spontaneous circulation. Chalak et al. reported that an ECO2 of 14 mmHg was the most reliable indicator for return of spontaneous circulation with 92% sensitivity and 81% specificity [21]. This study suggests that monitoring ECO2 during cardiopulmonary resuscitation would allow uninterrupted chest compression and potentially could be an indirect indicator of the CC effectiveness. This has been further supported by a recent animal study by Li et al., suggesting that either ECO2, rate of elimination of CO2 (VCO2) or partial pressure of exhaled (PeCO2) could be used to monitor the return of spontaneous circulation [12]. A recent case report of neonatal cardiopulmonary resuscitation in an extremely preterm infant supports this hypothesis where a significant increase in ECO2 preceded an increase in heart rate and return of spontaneous circulation [12]. ECO2 monitoring is a non-invasive tool that can be used to predict the return of spontaneous circulation during cardiopulmonary resuscitation.

**Figure 4.** Increasing ECO2 values suggesting imminent ROSC.

#### **5.1. Partial pressure of exhaled (PeCO2) and rate of elimination of CO2 (VCO2)**

A recent animal study described VCO2 and PECO2 values as a clinical indicator during chest compression to achieve the return of spontaneous circulation. VCO2, or the volume of expired CO2, reflects changes in both ventilation and perfusion, and therefore ventilation/perfusion (V/Q) matching [22]. Palme-Kilander et al. reported that low VCO2 values could be due to residual lung fluid, very low tone, or deficient perfusion of the lungs [23]. A recent study in preterm infants reported that higher VCO2 levels were associated with lung aeration and successful establishment of functional residual capacity [19]. During chest compression, increasing VCO2 values reflects adequate ventilation, perfusion, and lung aeration [22]. Thus, VCO2 potentially provides valuable information during neonatal resuscitation.

PeCO2 is a continuous, non-invasive measurement. Since the physiological dead space/tidal volume (*V*D/*V*T) ratio is never zero, PeCO2 is always lower than the ETCO2 [22]. During resuscitation, there is poor ventilation to perfusion matching, and therefore dead space/tidal volume increases, independent of whether mismatching is either due to impaired perfusion, impaired ventilation, or a mixture of impaired perfusion and ventilation, causing lower PeCO2 [22]. Therefore, PeCO2 is decreased under all conditions of impaired ventilation/ perfusion. In the case of ventilation mismatch, PeCO2 is dilute relative to ETCO2, and the PeCO2/ETCO2 ratio is reduced. In the case of reduced or maldistributed pulmonary blood flow without airway defects, both PeCO2 and ETCO2 would be reduced, resulting in a near normal PeCO2/ETCO2 ratio. A recent animal study described PeCO2 for the first time in the neonatal population. Newborn piglets who successfully achieved return of spontaneous circulation had significantly higher PeCO2 levels in the latter portion of cardiopulmonary resuscitation, indicating sufficient gas exchange was occurring [22]. Low levels of PeCO2 can only be attributed to poor or low quality of ventilation during cardiopulmonary resuscitation, while decreased levels of both PeCO2 and ETCO2 may signify inadequate pulmonary perfusion due to poor circulation [22]. These findings suggest that monitoring PeCO2 and ETCO2 continu‐ ously during cardiopulmonary resuscitation, the clinical team would be able to determine changes in ventilation or perfusion and adjust ventilation to improve either.

### **6. Conclusion**

that can be used to predict the return of spontaneous circulation during cardiopulmonary

resuscitation.

6 Respiratory Management of Newborns

**Figure 4.** Increasing ECO2 values suggesting imminent ROSC.

**5.1. Partial pressure of exhaled (PeCO2) and rate of elimination of CO2 (VCO2)**

VCO2 potentially provides valuable information during neonatal resuscitation.

A recent animal study described VCO2 and PECO2 values as a clinical indicator during chest compression to achieve the return of spontaneous circulation. VCO2, or the volume of expired CO2, reflects changes in both ventilation and perfusion, and therefore ventilation/perfusion (V/Q) matching [22]. Palme-Kilander et al. reported that low VCO2 values could be due to residual lung fluid, very low tone, or deficient perfusion of the lungs [23]. A recent study in preterm infants reported that higher VCO2 levels were associated with lung aeration and successful establishment of functional residual capacity [19]. During chest compression, increasing VCO2 values reflects adequate ventilation, perfusion, and lung aeration [22]. Thus, Using a respiratory function monitor to assess mask leak and tidal volume delivery during neonatal cardiopulmonary resuscitation can help improve mask ventilation. In addition, using exhaled carbon dioxide can predict return of spontaneous circulation during neonatal cardiopulmonary resuscitation.

## **Abbreviations**

## **Acknowledgements**

MOR is supported by a Molly Towell Perinatal Research Foundation Fellowship. ALS is supported by the Canadian Institute of Health Research (MOP299116) and the South-Eastern Norway Regional Health Authority. GMS is a recipient of the Heart and Stroke Foundation/ University of Alberta Professorship of Neonatal Resuscitation and Heart and Stroke Foundation Canada Research Scholar.

Conflict of Interest: None declared by the authors.

## **Author details**

Georg M Schmölzer1,2\*, Anne Solevåg1,2, Erica McGinn1 , Megan O'Reilly1,3 and Po-Yin Cheung1,2

\*Address all correspondence to<EMAIL_ADDRESS>
1 Centre for the Studies of Asphyxia and Resuscitation, Neonatal Research Unit, Royal Alexandra Hospital, Edmonton, Alberta, Canada

2 Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada

3 Department of Physiology, University of Alberta, Edmonton, Alberta, Canada

## **References**

[5] Schmölzer GM, Dawson JA, Kamlin COF, O'Donnell CP, Morley CJ, Davis PG. Airway obstruction and gas leak during mask ventilation of preterm infants in the delivery room. Arch Dis Child Fetal Neonatal 2011;96:F254–7.

**Acknowledgements**

8 Respiratory Management of Newborns

**Author details**

Po-Yin Cheung1,2

**References**

Foundation Canada Research Scholar.

Conflict of Interest: None declared by the authors.

Georg M Schmölzer1,2\*, Anne Solevåg1,2, Erica McGinn1

Alexandra Hospital, Edmonton, Alberta, Canada

Clin Perinatol 2012;39:833–42.

lation 2015;132:S204–41.

infants. Pediatrics 2000;106:618–20.

\*Address all correspondence to<EMAIL_ADDRESS>
MOR is supported by a Molly Towell Perinatal Research Foundation Fellowship. ALS is supported by the Canadian Institute of Health Research (MOP299116) and the South-Eastern Norway Regional Health Authority. GMS is a recipient of the Heart and Stroke Foundation/ University of Alberta Professorship of Neonatal Resuscitation and Heart and Stroke

1 Centre for the Studies of Asphyxia and Resuscitation, Neonatal Research Unit, Royal

[1] Kapadia V, Wyckoff MH. Chest compressions for bradycardia or asystole in neonates.

[2] Wyckoff MH, Perlman J. Cardiopulmonary resuscitation in very low birth weight

[3] Perlman J, Wyllie JP, Kattwinkel J, Wyckoff MH, Aziz K, Guinsburg R, et al. Part 7: Neonatal resuscitation: 2015 International consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. Circu‐

[4] Schmölzer GM, Kamlin COF, O'Donnell CP, Dawson JA, Morley CJ, Davis PG. Assessment of tidal volume and gas leak during mask ventilation of preterm infants in

the delivery room. Arch Dis Child Fetal Neonatal 2010;95:F393–7.

2 Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada

3 Department of Physiology, University of Alberta, Edmonton, Alberta, Canada

, Megan O'Reilly1,3 and

## **Chapter 2**

## **Alternative Therapies for the Management of Respiratory Distress Syndrome**

Alejandro González-Garay and Vicente González-Bustamante

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/63384

#### **Abstract**

[17] Blank D, Rich W, Leone TA, Garey D, Finer N. Pedi-cap color change precedes a significant increase in heart rate during neonatal resuscitation. Resuscitation

[18] Hooper SB, Fouras A, Siew M, Wallace MJ, Kitchen M, te Pas A, et al. Expired CO2 levels

[19] Kang LJ, Cheung P-Y, Pichler G, O'Reilly M, Aziz K, Schmölzer GM. Monitoring lung aeration during respiratory support in preterm infants at birth. PLoS One

[20] Kong JY, Rich W, Finer N, Leone TA.  J Pediatr 2013;163:104–8.e1.

[21] Chalak LF, Barber CA, Hynan L, Garcia D, Christie L, Wyckoff MH. End-tidal CO2 detection of an audible heart rate during neonatal cardiopulmonary resuscitation after

[22] Li ES-S, Cheung P-Y, O'Reilly M, LaBossiere J, Lee T-F, Cowan S, et al. Exhaled CO2 parameters as a tool to assess ventilation-perfusion mismatching during neonatal resuscitation in a swine model of neonatal asphyxia. PLoS One 2016;11:e0146524–11.

[23] Palme-Kilander C, Tunell R, Chiwei Y. Pulmonary gas exchange immediately after

birth in spontaneously breathing infants. Arch Dis Child 1993;68:6–10.

indicate degree of lung aeration at birth. PLoS One 2013;8:e70895.

asystole in asphyxiated piglets. Pediatr Res 2011;69:401–5.

2014;85:1568–72.

10 Respiratory Management of Newborns

2014;9:e102729.

Respiratory distress syndrome (RDS) is a disorder caused by a deficiency of surfaceactive agent called pulmonary surfactant, in the pulmonary alveoli. This deficiency leads the alveoli to collapse, impeding air entry, gas exchange, and oxygenation in newborns. Conventional treatment involves exogenous surfactant administration, ventilation, and hydroelectrolytic management.

However, there are alternative treatments to prevent RDS that can be administered to pregnant women (steroids, thyrotropin-releasing hormone, and ambroxol) or to newborns in their first few hours of life (continuous positive airway pressure, prophylactic surfactant in single or multiple doses, and digoxin). These approaches may be effective and cost less than conventional treatment. Conventional treatment requires trained medical personnel to attend to the newborn, ventilation, tempera‐ ture control, and electrolytic and nutritional support, which can cost up to USD 14,226 per event.

This chapter seeks to analyze the effectiveness of each of these alternative treatments in preventing RDS in preterm newborns, so that it can be applied in communities with limited resources.

**Keywords:** ambroxol, respiratory distress syndrome, antenatal steroids, preterm birth, alternative therapies

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **1. Introduction**

The lungs are composed of different structures. The alveoli are the functional units of the lungs that allow oxygen gas (O2) from the environment to be exchanged for carbon dioxide (CO2) from the bloodstream.

In order for this process to take place, contact between the air-filled alveoli and the capillaries of the lung is essential. However, certain conditions can affect this process by preventing air from entering the alveoli, diminishing blood flow in pulmonary capillaries, or impeding alveolus-capillary contact, which hampers gas exchange and leads to decreased O2 and increased CO2 levels in the blood [1].

Alveoli comprise (a) type I pneumocytes, cells that provide shape and support and (b) type II pneumocytes, cells responsible for producing the surface-active agent called pulmonary surfactant. A surfactant is a substance made up of phospholipids (80%), proteins (12%), and neutral lipids (8%). Surfactants decrease the surface tension inside the alveoli. When there is insufficient surfactant, the alveoli collapse, preventing air entry and gas exchange. This is accompanied by a decrease in O2 in the tissues and a gradual increase in respiratory effort, leading to this disorder being known as respiratory distress syndrome (RDS) [1–3].

This disorder affects up to 30% of premature newborns (<37 weeks of gestation) and accounts for 9.3–12% of hospital admissions to neonatal intensive care units [4–6]. Some studies have reported that the following factors are linked to the development of RDS: birth by cesarean section, gestational diabetes, meconium aspiration, and neonatal asphyxia [7].

Conventional treatment, which has been shown to reduce mortality rates by up to 18%, involves the exogenous administration of natural or synthetic surfactant at a dose of 100 mg/kg, up to 2–3 times, once RDS is diagnosed. The treatment also involves the use of mechanical ventilation, temperature control in an incubator, and electrolytic and nutritional support. However, this treatment has multiple adverse effects, such as pneumothorax, bronchopulmonary dysplasia, and retinopathy secondary to ventilation support and the continuous administration of supplemental oxygen over prolonged periods, malnutrition, and infections [2, 8].

As a consequence, many researchers have studied alternatives to prevent the development of RDS and reduce the frequency of these complications.

## **2. Alternative treatments for the prevention of RDS**

The following are some treatments designed to prevent the development of RDS in newborns.

#### **2.1. Early administration of surfactant**

Numerous studies have reported that the administration of surfactant in the first few hours of life prior to the development of RDS reduces the mortality rate of preterm newborns. In 2012, Bahadue and Soll carried out a systematic review of six clinical trials involving 3577 preterm newborns and analyzed the effectiveness of administering surfactant in the first 2 hours of life. The authors found a significant reduction in the risk of death [RR 0.84 (0.74–0.95)] compared to delayed selective surfactant administration with neonates with established RDS [9] (**Figure 1**).

**Figure 1.** Early vs delayed administration of surfactant (risk of death).

**1. Introduction**

12 Respiratory Management of Newborns

from the bloodstream.

infections [2, 8].

increased CO2 levels in the blood [1].

The lungs are composed of different structures. The alveoli are the functional units of the lungs that allow oxygen gas (O2) from the environment to be exchanged for carbon dioxide (CO2)

In order for this process to take place, contact between the air-filled alveoli and the capillaries of the lung is essential. However, certain conditions can affect this process by preventing air from entering the alveoli, diminishing blood flow in pulmonary capillaries, or impeding alveolus-capillary contact, which hampers gas exchange and leads to decreased O2 and

Alveoli comprise (a) type I pneumocytes, cells that provide shape and support and (b) type II pneumocytes, cells responsible for producing the surface-active agent called pulmonary surfactant. A surfactant is a substance made up of phospholipids (80%), proteins (12%), and neutral lipids (8%). Surfactants decrease the surface tension inside the alveoli. When there is insufficient surfactant, the alveoli collapse, preventing air entry and gas exchange. This is accompanied by a decrease in O2 in the tissues and a gradual increase in respiratory effort,

This disorder affects up to 30% of premature newborns (<37 weeks of gestation) and accounts for 9.3–12% of hospital admissions to neonatal intensive care units [4–6]. Some studies have reported that the following factors are linked to the development of RDS: birth by cesarean

Conventional treatment, which has been shown to reduce mortality rates by up to 18%, involves the exogenous administration of natural or synthetic surfactant at a dose of 100 mg/kg, up to 2–3 times, once RDS is diagnosed. The treatment also involves the use of mechanical ventilation, temperature control in an incubator, and electrolytic and nutritional support. However, this treatment has multiple adverse effects, such as pneumothorax, bronchopulmonary dysplasia, and retinopathy secondary to ventilation support and the continuous administration of supplemental oxygen over prolonged periods, malnutrition, and

As a consequence, many researchers have studied alternatives to prevent the development of

The following are some treatments designed to prevent the development of RDS in newborns.

Numerous studies have reported that the administration of surfactant in the first few hours of life prior to the development of RDS reduces the mortality rate of preterm newborns. In 2012,

leading to this disorder being known as respiratory distress syndrome (RDS) [1–3].

section, gestational diabetes, meconium aspiration, and neonatal asphyxia [7].

RDS and reduce the frequency of these complications.

**2.1. Early administration of surfactant**

**2. Alternative treatments for the prevention of RDS**

Bahadue also analyzed adverse effects in patients that received early administration of surfactant and reported that there was a decrease in the risk of developing chronic lung disease [RR 0.69 (0.55–0.86)], pneumothorax [RR 0.69 (0.59–0.82)], pulmonary interstitial emphysema [RR 0.60 (0.41–0.89)], and bronchopulmonary dysplasia [RR 0.94 (0.88–1.00)] [9] (**Figures 2**–**5**).

**Figure 2.** Early vs delayed selective surfactant treatment (chronic lung disease).

**Figure 3.** Early vs delayed selective surfactant treatment (pneumothorax).

**Figure 4.** Early vs delayed selective surfactant treatment (pulmonary interstitial emphysema).

**Figure 5.** Early vs delayed selective surfactant treatment (bronchopulmonary dysplasia).

#### **2.2. Administration of multiple doses of surfactant**

**Figure 3.** Early vs delayed selective surfactant treatment (pneumothorax).

14 Respiratory Management of Newborns

**Figure 4.** Early vs delayed selective surfactant treatment (pulmonary interstitial emphysema).

**Figure 5.** Early vs delayed selective surfactant treatment (bronchopulmonary dysplasia).

Some researchers have carried out clinical trials to determine the effectiveness of administering multiple doses of surfactant to newborns to prevent RDS or reduce its complications. In 2009, Soll and Ozek carried out a systematic review to investigate whether this alternative treatment could decrease the risk of RDS and complications in preterm newborns. Only three clinical trials could be included in the review, but the authors concluded from these that there was a decrease in the risk of developing pneumothorax for neonates that received up to a maximum of four doses of surfactant spaced 6–12 hours apart compared to those who received single doses [RR 0.51 (0.30–0.88)]. There was a non-significant decrease in the risk of death for newborns who received multiple doses of surfactant [RR 0.63 (0.39–1.02)]. They concluded that the ability to give multiple doses of surfactant to infants with ongoing respiratory insufficiency leads to improved clinical outcome and appears to be the most effective treatment policy (**Figures 6** and **7**) [10].

**Figure 6.** Multiple vs single doses of pulmonary treatment (pneumothorax).

**Figure 7.** Multiple vs single doses of pulmonary surfactant (mortality).

### **2.3. Early application of continuous positive airway pressure (CPAP)**

CPAP is an alternative treatment for newborns with RDS that involves the application of a type of respiratory support that applies air at low pressure in a continuous manner to keep the airway open. This treatment increases functional residual capacity and oxygenation with fewer secondary effects [11].

It has been observed that this type of respiratory support carries a lower risk of secondary complications such as barotrauma, pneumothorax, and pulmonary emphysema, among others. Recent studies of CPAP application in premature neonates in the first few minutes of life have shown that the risk of death is lower [RR 0.68 (0.5–1.92)] than for neonates who receive conventional ventilation. It has also been reported that the early application of CPAP in patients who developed RDS and received conventional treatment reduced the duration of mechanical ventilation (25 vs. 28 days) [12].

These findings were confirmed in a systematic review by Bahadue, who reported that the early application of CPAP and the selective administration of surfactants in preterm neonates reduced the risk of death compared to newborns who received only prophylactic surfactant [RR 0.84 (0.74–0.95)] [9].

To study long-term outcomes, Vaucher and colleagues carried out a follow-up assessment at 22 months of 1310 neonates that had been treated with CPAP to prevent RDS and found a decrease in the frequency of neurological and respiratory problems compared to patients treated with conventional therapy involving mechanical ventilation [RR 0.93 (0.78–1.10)] [13], similar findings were observed in the prospective study performed by Stevens and colleagues in 918 infants; those who received CPAP had fewer episodes of wheezing, respiratory illnesses, and visits to emergency room for breathing problems compared to infants who received conventional therapy [28.9% vs. 36.5%, 47.7% vs. 55.2%, and 68% vs. 72.9% (*p* < 0.05), respec‐ tively] [14].

On the basis of these results, the American Academy of Pediatrics recommends the early use of CPAP in conjunction with surfactant administration as an alternative to prevent RDS in preterm newborns [15].

#### **2.4. Administration of digoxin**

In 1955, Lendrum suggested that cardiac insufficiency secondary to pulmonary edema was a predisposing factor for RDS. Several clinical trials were carried out to determine whether the administration of digoxin in the first few hours of life would improve heart contractility and reduce the risk of developing RDS [16, 17].

As part of a systematic review in 2011, Soll and Ozek analyzed the efficacy of digoxin appli‐ cation in preventing RDS at doses of 0.01–0.06 mg/kg every 12 hours in 212 preterm newborns. They found that, despite improvements to cardiac insufficiency, there was no significant reduction in mortality compared to newborns who did not receive digoxin [RR 1.27 (0.78– 2.07)]. The authors concluded that although hemodynamic disturbances play a role in the overall pathogenesis of RDS, the specific contribution of early congestive heart failure does not appear to be significant factor in RDS, and the treatment with digoxin has no proven value in infants solely affected with RDS [18] (**Figure 8**).

**Figure 8.** Digoxin vs placebo for preventing or treating respiratory distress syndrome (mortality).

**2.3. Early application of continuous positive airway pressure (CPAP)**

fewer secondary effects [11].

16 Respiratory Management of Newborns

[RR 0.84 (0.74–0.95)] [9].

preterm newborns [15].

**2.4. Administration of digoxin**

reduce the risk of developing RDS [16, 17].

tively] [14].

mechanical ventilation (25 vs. 28 days) [12].

CPAP is an alternative treatment for newborns with RDS that involves the application of a type of respiratory support that applies air at low pressure in a continuous manner to keep the airway open. This treatment increases functional residual capacity and oxygenation with

It has been observed that this type of respiratory support carries a lower risk of secondary complications such as barotrauma, pneumothorax, and pulmonary emphysema, among others. Recent studies of CPAP application in premature neonates in the first few minutes of life have shown that the risk of death is lower [RR 0.68 (0.5–1.92)] than for neonates who receive conventional ventilation. It has also been reported that the early application of CPAP in patients who developed RDS and received conventional treatment reduced the duration of

These findings were confirmed in a systematic review by Bahadue, who reported that the early application of CPAP and the selective administration of surfactants in preterm neonates reduced the risk of death compared to newborns who received only prophylactic surfactant

To study long-term outcomes, Vaucher and colleagues carried out a follow-up assessment at 22 months of 1310 neonates that had been treated with CPAP to prevent RDS and found a decrease in the frequency of neurological and respiratory problems compared to patients treated with conventional therapy involving mechanical ventilation [RR 0.93 (0.78–1.10)] [13], similar findings were observed in the prospective study performed by Stevens and colleagues in 918 infants; those who received CPAP had fewer episodes of wheezing, respiratory illnesses, and visits to emergency room for breathing problems compared to infants who received conventional therapy [28.9% vs. 36.5%, 47.7% vs. 55.2%, and 68% vs. 72.9% (*p* < 0.05), respec‐

On the basis of these results, the American Academy of Pediatrics recommends the early use of CPAP in conjunction with surfactant administration as an alternative to prevent RDS in

In 1955, Lendrum suggested that cardiac insufficiency secondary to pulmonary edema was a predisposing factor for RDS. Several clinical trials were carried out to determine whether the administration of digoxin in the first few hours of life would improve heart contractility and

As part of a systematic review in 2011, Soll and Ozek analyzed the efficacy of digoxin appli‐ cation in preventing RDS at doses of 0.01–0.06 mg/kg every 12 hours in 212 preterm newborns. They found that, despite improvements to cardiac insufficiency, there was no significant reduction in mortality compared to newborns who did not receive digoxin [RR 1.27 (0.78– 2.07)]. The authors concluded that although hemodynamic disturbances play a role in the overall pathogenesis of RDS, the specific contribution of early congestive heart failure does

#### **2.5. Administration of thyrotropin-releasing hormone and antenatal steroids**

In 1972, Liggins and Howie demonstrated that the administration of steroids (betamethasone) to pregnant women at risk of giving birth prematurely reduced the risk of their newborns developing RDS [RR 0.69 (0.59–0.73)] because the steroid passes through the placenta, reaches the fetal pulmonary alveoli, and stimulates the production of surfactant by type II pneumo‐ cytes. However, the use of this treatment did not become commonplace until 1987. It has since reduced the rate of neonatal mortality and is the preventive therapy of choice for obstetricians [19, 20].

Later, Liggins found that the administration of thyrotropin-releasing hormone (TRH) in combination with antenatal steroids increased the production of phospholipids and the distension of fetal sheep' lungs [19]. In 2013, Crowther carried out a systematic review analyzing 4600 pregnant women who were administered TRH and steroids prior to delivery. However, no significant differences were observed in terms of reducing the risk of death for premature newborns [RR 1.05 (0.86–1.27)] (**Figure 9**) or prevention of RDS compared to neonates born to women who received antenatal betamethasone therapy [RR 1.05 (0.91–1.22)] (**Figure 10**). However, it was observed that the administration of the combination of TRH and antenatal steroids did significantly increase the risk of adverse effects such as nausea, vomiting, and headaches [RR 3.92 (3.13–4.92), RR 2.35 (1.35–4.09), and RR 1.73 (1.36–2.22), respectively] (**Figures 11**–**13**) [21].

**Figure 9.** Thyrotropin-releasing hormone + steroids vs steroids alone for RDS (mortality).

**Figure 10.** Thyrotropin-releasing hormone + steroids vs steroids alone for respiratory distress syndrome.

**Figure 11.** Thyrotropin-releasing hormone + steroids vs steroids alone for RDS (nausea).

**Figure 12.** Thyrotropin-releasing hormone + steroids vs steroids alone for RDS (vomiting).

**Figure 13.** Thyrotropin-releasing hormone + steroids vs steroids alone for RDS (headaches).

#### **2.6. Administration of magnesium sulfate**

The administration of magnesium sulfate to pregnant women is used by obstetricians to inhibit labor and birth before 37 weeks of gestation by altering the union and distribution of calcium in the muscle fibers of the uterus, thus reducing the frequency of contractions [22].

In 2015, McNamara carried out a systematic review to analyze the efficacy and safety of magnesium sulfate (4 g loading dose and 2–5 g/h via infusion) administered to 360 pregnant women at less than 37 weeks of gestation to inhibit preterm labor. McNamara observed that this treatment reduces the risk of developing RDS [RR 0.31 (0.11–0.88)] and decreases the time that neonates spend in intensive care [MD −3.10 (0–5.48 to −0.72 days)]. However, there is too little evidence available to recommend the regular use of this treatment (**Figures 14** and **15**) [23].

**Figure 14.** Magnesium sulfate for respiratory distress syndrome.

**Figure 15.** Magnesium sulfate for RDS (days of stay neonatal intensive care unit).

#### **2.7. Administration of ambroxol**

**Figure 10.** Thyrotropin-releasing hormone + steroids vs steroids alone for respiratory distress syndrome.

18 Respiratory Management of Newborns

**Figure 11.** Thyrotropin-releasing hormone + steroids vs steroids alone for RDS (nausea).

**Figure 12.** Thyrotropin-releasing hormone + steroids vs steroids alone for RDS (vomiting).

**Figure 13.** Thyrotropin-releasing hormone + steroids vs steroids alone for RDS (headaches).

Ambroxol is a metabolite derived from bromhexine that increases the movement of cilia in the cells of the respiratory tract, facilitating the transport of mucus in the airway and inhibiting the activity of lysosomal phospholipase, the enzyme responsible for the degradation of pulmonary surfactant [24].

Laoag-Fernandez and Seifart carried out several clinical studies to analyze the effectiveness of ambroxol as an alternative treatment in the prevention of RDS because it allows easily reaching the fetus through placental circulation. These studies allowed Gonzalez to carry out a system‐ atic review in 2014 [25].

The systematic review included 14 clinical trials analyzing 1047 pregnant women at risk of preterm birth who were administered a daily 1 g dose of ambroxol for a week.

The results of the review showed a reduction in the risk of neonates developing RDS compared to treatments in which women were administered antenatal steroids (betamethasone) or a placebo [RR 0.79 (0.59–1.07) and RR 0.74 (0.46–1.20), respectively] (**Figures 16** and **17**) [25].

**Figure 16.** Ambroxol vs betamethasone for respiratory distress syndrome.

**Figure 17.** Ambroxol vs placebo or no treatment for respiratory distress syndrome.

#### **3. Conclusions**

We can see that although there are multiple alternative treatment options to prevent preterm newborns from developing RDS, their effectiveness has not yet been proven (with the exception of prenatal steroid administration) with evidence that is strong enough due to a lack of studies with larger numbers of participants and sound methodology. Nevertheless, it is possible that these might be viable treatments in communities that do not have the financial resources or the medical care required to attend to these patients. Conventional treatments require trained medical personnel who can attend deliveries and care for premature neonates in hospital units that have the necessary infrastructure as well as mechanical ventilators, temperature control systems, antibiotics for infection control, and intravenous solutions to maintain nutritional and hydroelectrolytic homeostasis.

In 2014, Martínez-Valverde and colleagues carried out a study to estimate the costs of provid‐ ing care to newborns with RDS in public hospitals in Mexico and found that, on average, the cost per patient per event can reach USD 14,226, without accounting for the cost of treating secondary conditions [26].

Undoubtedly, more studies need to be carried out to strengthen the evidence supporting the use of these alternative treatments. However, they could be a sustainable option in commun‐ ities with limited financial resources because they are more readily available and have fewer adverse effects and lower costs than conventional treatment.

## **Author details**

The results of the review showed a reduction in the risk of neonates developing RDS compared to treatments in which women were administered antenatal steroids (betamethasone) or a placebo [RR 0.79 (0.59–1.07) and RR 0.74 (0.46–1.20), respectively] (**Figures 16** and **17**) [25].

**Figure 16.** Ambroxol vs betamethasone for respiratory distress syndrome.

**Figure 17.** Ambroxol vs placebo or no treatment for respiratory distress syndrome.

We can see that although there are multiple alternative treatment options to prevent preterm newborns from developing RDS, their effectiveness has not yet been proven (with the exception of prenatal steroid administration) with evidence that is strong enough due to a lack of studies with larger numbers of participants and sound methodology. Nevertheless, it is possible that these might be viable treatments in communities that do not have the financial resources or the medical care required to attend to these patients. Conventional treatments

**3. Conclusions**

20 Respiratory Management of Newborns

Alejandro González-Garay1\* and Vicente González-Bustamante2

\*Address all correspondence to<EMAIL_ADDRESS>
1 Methodology Research Unit, National Institute of Pediatrics, Mexico City, Mexico

2 Autonomous Metropolitan University, Mexico City, Mexico

## **References**

[18] Soll R, Özek E. Digoxin for preventing or treating neonatal respiratory distress syndrome. Cochrane Database of Systematic Reviews 2011, Issue 1. Art. No.: CD001080. DOI: 10.1002/14651858.CD001080.pub2

[6] Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. CochraneDatabase of Systematic Reviews 2006;

[7] Hansen T, Corbet A. Disorders of the transition. In: Taeush W, Ballard R editor(s).

[8] Udaeta E, Alfaro M. Respiratory Distress Syndrome in the newborn. Neonatology

[9] Bahadue FL, Soll R. Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome. Cochrane Database of Systematic Reviews 2012, Issue

[10] Soll R, Özek E. Multiple versus single doses of exogenous surfactant for the prevention or treatment of neonatal respiratory distress syndrome. Cochrane Database of System‐

[11] Piñeros J, Correa M, Andrade M, Roa M. Neonatal Respiratory Distress by deficit of surfactant. In: Ucrós S, Mejía N editors. Pediatrics practice evidence-based guides 2a. Ed. Colombia: Editorial Médica Panamericana, 2009:62–5. ISBN: 978–9588443–02–7.

[12] Morley C, Davis P, Doyle L, Brion L, Hascoet J, Carlin J; COIN Trial Investigators. Nasal CPAP or intubation at birth for very preterm infants. New England Journal of Medicine

[13] Vaucher Y, Peralta-Carcelen M, Finer NN; SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network. Neurodevelopmental out‐ comes in the early CPAP and pulse oximetry trial. New England Journal of Medicine

[14] Stevens T, Finer N, Carlo W, Szilagyi P, Phelps D, Walsh M, et al. Respiratory outcomes of the surfactant positive pressure and oximetry randomized trial (SUPPORT). Journal

[15] Committe on Fetus and Newborn; American Academy of Pediatrics. Respiratory support in preterm infants at birth. Pediatrics 2014;13381:171–174. DOI: 10.1542/peds.

[16] Lendrum FC. The 'pulmonary hyaline membrane' as a manifestation of heart failure in the newborn infant. Journal of Pediatrics 1955;47:149–156. DOI: 10.1016/

[17] Stahlman MT. Adaptation to Extra-Uterine Life. Report of 31st Ross Conference on Pediatric Research. Columbus, OH: Ross Laboratories, 1959. Class Number: WS 420

of Pediatrics 2014;165(2):240–249.e4. DOI: 10.1016/j.jpeds.2014.02.054

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Avery's Diseases of the Newborn. 7a. Mexico: Harcourt, 2000: 602–13.

Clínic. Mexico: McGraw Hill, 2004:250–80. ISBN:<PHONE_NUMBER>.

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(3):CD004454.

22 Respiratory Management of Newborns

2013-3442

R823A 1958.

S0022-3476(55)80025-X

## **Respiratory Management of the Newborn with an Omphalocele**

Joanne Baerg, Arul Thirumoorthi and Andrew Hopper

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/63735

#### **Abstract**

Despite advances in neonatal care, infants with omphalocele have a mortality rate ranging between 5% and 25%. Respiratory insufficiency is a common clinical chal‐ lenge and an independent predictor of mortality in these infants. The causes of respiratory failure are diverse and are not well understood. This chapter discusses the unique aspects of respiratory management in omphalocele infants. The authors have chosen references in this chapter with appropriate sample size, variable comparisons, regression analyses, and documented median follow-up times. Omphalocele is rare; therefore, the case reports of chapter references have important information.

Omphalocele infants are sometimes born with inadequate lung volume to support survival. Prenatal predictors of pulmonary hypoplasia are discussed in the context of fetal magnetic resonance imaging (MRI) and postnatal clinical-radiologic correlation studies. Two recent retrospective articles explain the unique aspects of pulmonary hypertension in omphalocele infants and distinguish it from pulmonary hypoplasia. The avoidance of abdominal compartment syndrome at the time of omphalocele closure is discussed. Clinical strategies that improve the respiratory care of these infants, based on Specific definitions and diagnoses, may reduce the high mortality rate.

**Keywords:** respiratory insufficiency, pulmonary hypoplasia, pulmonary hyperten‐ sion, abdominal compartment syndrome, extracorporeal membrane oxygenator, de‐ layed repair

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **1. Introduction**

Omphalocele is a congenital ventral defect of the umbilical ring with herniation of the abdominal viscera. The reported incidence is 1 in 6000 live births [1]. If omphalocele is diagnosed in the first trimester, over 30% of fetuses die in utero [2, 3]. Despite advances in neonatal care, for live-born infants, the mortality rate remains between 5% and 25% [4].

Postnatal management includes protection of the herniated viscera, prevention of hypother‐ mia, gastric decompression, and maintenance of cardiopulmonary stability [5].

Respiratory insufficiency at birth is reported as an independent predictor of mortality for infants with omphalocele, but the causes are diverse [1]. Respiratory insufficiency in neonates is generally defined as hypoxemia in room air with progressive respiratory and metabolic acidosis and the need for mechanical ventilation within 24 hours of birth [1].

In this chapter, giant and nongiant omphaloceles are compared, as giant omphalocele infants have a more complex postnatal course and more respiratory difficulties.

Prenatal predictors of postnatal respiratory failure and unique clinical care strategies are discussed. Pulmonary hypoplasia is defined. Historically, fetuses and infants with omphalo‐ cele are reported to have markedly reduced chest capacities. Recently, fetal magnetic resonance imaging (MRI) has expanded the understanding of decreased congenital lung volume in infants with omphaloceles. Clinical-radiologic correlation studies support the use of prenatal MRI to predict the degree of respiratory insufficiency observed in the postnatal period.

The contribution of major anomalies to respiratory difficulties is discussed.

Infants with omphalocele may have increased pulmonary vascular reactivity and pulmonary hypertension that increases the postnatal mortality risk. In this chapter, pulmonary hypoplasia and pulmonary hypertension are defined as distinct entities. The chapter emphasizes that the two diagnoses must be distinguished from each other in the clinical setting. Each has different clinical implications and care strategies.

The implications of congenital heart defects in omphalocele infants are explained. The roles and goals of assisted ventilation for respiratory insufficiency in omphalocele infants are expanded.

Since 2011, a small number of infants with omphalocele and respiratory insufficiency have required the extra-corporeal membrane oxygenator (ECMO) for respiratory failure. This chapter provides the first review of the Extra-corporeal Life Support Organization (ELSO, Ann Arbor, MI, USA) database for the causes of respiratory failure and outcomes in omphalocele infants place on ECMO.

The timing of surgical repair and postoperative complications, such as compartment syn‐ drome, delayed surgical closure techniques, and the implications of a ruptured omphalocele, are explained.

Pulmonary function abnormalities, chronic lung disease, the role of tracheostomy, the influence of gastroesophageal reflux disease (GERD), prematurity, and strategies to improve outcomes, are discussed.

## **2. Giant omphalocele**

**1. Introduction**

26 Respiratory Management of Newborns

Omphalocele is a congenital ventral defect of the umbilical ring with herniation of the abdominal viscera. The reported incidence is 1 in 6000 live births [1]. If omphalocele is diagnosed in the first trimester, over 30% of fetuses die in utero [2, 3]. Despite advances in neonatal care, for live-born infants, the mortality rate remains between 5% and 25% [4].

Postnatal management includes protection of the herniated viscera, prevention of hypother‐

Respiratory insufficiency at birth is reported as an independent predictor of mortality for infants with omphalocele, but the causes are diverse [1]. Respiratory insufficiency in neonates is generally defined as hypoxemia in room air with progressive respiratory and metabolic

In this chapter, giant and nongiant omphaloceles are compared, as giant omphalocele infants

Prenatal predictors of postnatal respiratory failure and unique clinical care strategies are discussed. Pulmonary hypoplasia is defined. Historically, fetuses and infants with omphalo‐ cele are reported to have markedly reduced chest capacities. Recently, fetal magnetic resonance imaging (MRI) has expanded the understanding of decreased congenital lung volume in infants with omphaloceles. Clinical-radiologic correlation studies support the use of prenatal MRI to predict the degree of respiratory insufficiency observed in the postnatal period.

Infants with omphalocele may have increased pulmonary vascular reactivity and pulmonary hypertension that increases the postnatal mortality risk. In this chapter, pulmonary hypoplasia and pulmonary hypertension are defined as distinct entities. The chapter emphasizes that the two diagnoses must be distinguished from each other in the clinical setting. Each has different

The implications of congenital heart defects in omphalocele infants are explained. The roles and goals of assisted ventilation for respiratory insufficiency in omphalocele infants are

Since 2011, a small number of infants with omphalocele and respiratory insufficiency have required the extra-corporeal membrane oxygenator (ECMO) for respiratory failure. This chapter provides the first review of the Extra-corporeal Life Support Organization (ELSO, Ann Arbor, MI, USA) database for the causes of respiratory failure and outcomes in omphalocele

The timing of surgical repair and postoperative complications, such as compartment syn‐ drome, delayed surgical closure techniques, and the implications of a ruptured omphalocele,

mia, gastric decompression, and maintenance of cardiopulmonary stability [5].

acidosis and the need for mechanical ventilation within 24 hours of birth [1].

have a more complex postnatal course and more respiratory difficulties.

The contribution of major anomalies to respiratory difficulties is discussed.

clinical implications and care strategies.

expanded.

infants place on ECMO.

are explained.

Giant omphalocele represents an important subset of omphalocele infants. Giant omphalocele is defined as an omphalocele defect containing greater than 75% liver in the sac, and/or a diameter greater than 5 cm [4, 6]. A nongiant omphalocele is generally defined as a defect with diameter less than 5 cm. Previous definitions that measured the defect in centimeters do not account for the differences in size and gestational age of infants.

The definition that giant omphalocele is a defect that contains greater than 75% liver in the sac is preferable and uniform [4]. Giant omphalocele is associated with poor prognosis in many studies. Giant omphalocele is often associated with a greater incidence of respiratory insuffi‐ ciency, longer ventilator requirements, and an increased incidence of pulmonary hypoplasia and pulmonary hypertension [6, 7].

Infants with giant omphaloceles have significantly more neonatal morbidity. When large and small omphaloceles are compared, the median length of stay (47 vs. 10 days), median age at full enteral feeds (23 vs. 5 days), median duration of mechanical ventilation (23 vs.7 days), and requirement of supplemental oxygen at 30 days of life (88% vs. 27%) are significantly longer for infants with giant omphaloceles [7].

Respiratory failure is the major cause of mortality in infants with giant omphaloceles [8]. In the neonatal period, these infants have significantly more pulmonary hypoplasia and pulmo‐ nary hypertension and therefore, more respiratory difficulties [4, 7, 9]. Lung preservation ventilation strategies are emphasized in infants with giant omphaloceles. The overall inhospital mortality for infants with giant omphaloceles approaches 20% [6].

After the neonatal period, giant omphalocele infants have more chronic lung disease and gastroesophageal reflux. In contrast, small omphaloceles generally have a good prognosis when they are not associated with lethal malformations or congenital syndromes [5].

Most minor defects are closed primarily. Because of the preponderance for respiratory insufficiency in infants with giant omphaloceles, however, there is more controversy regarding closure techniques.

Infants with giant omphaloceles have suboptimal neurodevelopmental outcomes. Their difficult early course frequently includes hypoxia, acidosis, hypotension during delivery, a long duration of mechanical ventilation, infection, and prolonged hospitalization. These factors all compound and play a role in determining neurologic outcomes.

Giant omphalocele survivors tend to have more significant neurodevelopmental delay than children with other congenital anomalies such as congenital diaphragmatic hernia or congen‐ ital heart defects. They appear similar in their neurocognitive outcomes to preterm newborns that develop severe bronchopulmonary dysplasia. This further emphasizes the importance of optimal respiratory management and an understanding of the goals of assisted ventilation for infants with giant omphaloceles [6].

## **3. Pulmonary hypoplasia and the role of fetal magnetic resonance imaging**

Lung hypoplasia is defined as insufficient development of pulmonary airways, alveoli, and vessels [10]. Historically, plain chest radiographs of omphalocele infants revealed a narrow thorax and curved ribs. Measures of chest width and lung area were significantly smaller in giant omphalocele infants. Such abnormalities of lung growth may be the result of a defor‐ mation sequence in utero. The liver is displaced in giant omphaloceles and so does not mold the thoracic cage [11–13].

Subsequently, prenatal ultrasound was used to calculate observed/expected lung volumes for fetuses. Two-dimensional ultrasound measured the lung-to-thorax ratio and predicted pulmonary hypoplasia. However, some report the assessment as inaccurate [14]. Threedimensional ultrasound has improved sensitivity in normal amniotic fluid volume but not oligohydramnios [15, 16].

Presently, fetal magnetic resonance imaging studies have established a curve of normal fetal lung volume values plotted against gestational age [17]. The measured fetal lung volume is divided by the expected mean fetal lung volume for a given gestational age or fetal body volume to obtain the observed/expected total fetal lung volume (O/E-TFLV) ratio [17].

Accurate measurement of fetal lung volume has important clinical applications. Fetal magnetic resonance imaging has shown that lung volumes are only 50% of the predicted values in some prematurely born omphalocele infants with large defects. Such infants have lower Apgar scores and require prolonged ventilator support [18].

When infants with congenital lung malformations (CLMs), congenital diaphragmatic hernias (CDHs), or omphaloceles and an O/E-TFLV of 40% to 60% are compared, the need for ECMO, the use of supplemental oxygen at 30 days of life, and the 6-month mortality are similar among the three groups (**Table 1**) [19].

that develop severe bronchopulmonary dysplasia. This further emphasizes the importance of optimal respiratory management and an understanding of the goals of assisted ventilation for

Lung hypoplasia is defined as insufficient development of pulmonary airways, alveoli, and vessels [10]. Historically, plain chest radiographs of omphalocele infants revealed a narrow thorax and curved ribs. Measures of chest width and lung area were significantly smaller in giant omphalocele infants. Such abnormalities of lung growth may be the result of a defor‐ mation sequence in utero. The liver is displaced in giant omphaloceles and so does not mold

Subsequently, prenatal ultrasound was used to calculate observed/expected lung volumes for fetuses. Two-dimensional ultrasound measured the lung-to-thorax ratio and predicted pulmonary hypoplasia. However, some report the assessment as inaccurate [14]. Threedimensional ultrasound has improved sensitivity in normal amniotic fluid volume but not

Presently, fetal magnetic resonance imaging studies have established a curve of normal fetal lung volume values plotted against gestational age [17]. The measured fetal lung volume is divided by the expected mean fetal lung volume for a given gestational age or fetal body volume to obtain the observed/expected total fetal lung volume (O/E-TFLV) ratio [17].

Accurate measurement of fetal lung volume has important clinical applications. Fetal magnetic resonance imaging has shown that lung volumes are only 50% of the predicted values in some prematurely born omphalocele infants with large defects. Such infants have lower Apgar

When infants with congenital lung malformations (CLMs), congenital diaphragmatic hernias (CDHs), or omphaloceles and an O/E-TFLV of 40% to 60% are compared, the need for ECMO, the use of supplemental oxygen at 30 days of life, and the 6-month mortality are similar among

**Omphalocele**

9.0 (7–17) 0 (0–6)\* 0 (0–1.3)\* <0.001

29.0 (22–55) 30.5 (15–47) 8.0 (3–20)\*# 0.009

**CLM** *n* **= 16** *p***-value**

*n* **= 13**

*n* **= 27**

**3. Pulmonary hypoplasia and the role of fetal magnetic resonance**

infants with giant omphaloceles [6].

28 Respiratory Management of Newborns

**imaging**

the thoracic cage [11–13].

oligohydramnios [15, 16].

the three groups (**Table 1**) [19].

Length of intubation, days

Length of hospital stay, days

median (IQR)

median (IQR)

**Variable CDH**

scores and require prolonged ventilator support [18].

IQR: interquartile range; HTN: hypertension; iNO: inhaled nitric oxide; ECMO: extra-corporeal membrane oxygenation; supplemental O2 at 30 DOL: supplemental oxygen at 30 days of life \* *p* < 0.05 vs. CDH. # *p* < 0.05 vs. OM.

**Table 1.** Outcomes of congenital diaphragmatic hernia (CDH), omphalocele (OM), and congenital lung malformation (CLM) in infants with fetal lung volumes between 40% and 60% of predicted values [19].

In fetuses with CLM, an O/E-TFLV of less than 75% after 26 weeks predicts a difficult postnatal course that includes increased respiratory distress, a need for intubation, and lung mass excision [20].

Infants with CDH generally have O/E-TFLV measurements ranging from less than 25% to 45%. They require more pulmonary support than omphalocele and congenital lung malformation infants. Clinical-radiologic correlation studies support the use of prenatal MRI to predict the perinatal and postnatal courses in neonates with CDH. The measurements have also been used to guide the fetal therapy with improved postnatal results. Ratios less than 35% are associated with an increased use of ECMO and a higher mortality [21].

A series of infants with giant omphaloceles compare those with less than 50% to infants with greater than 50% O/E-TFLV at 26 to 31 weeks gestational age. Infants with less than 50% O/E-TFLV have significantly lower Apgar scores at birth, prolonged ventilation, and a longer hospitalization. MRI-based O/E-TFLV of less than 50% is considered predictive of increased postnatal morbidity in giant omphalocele infants [18].

A precise quantification of compromised fetal lung development in omphalocele infants may improve perinatal and postnatal management. Fetal magnetic resonance imaging after 26 weeks gestational age and calculation of the O/E-TFLV is recommended.

Similar to CDH and CLM, this calculation reflects pulmonary hypoplasia and allows clinicians to prepare for increased respiratory distress, a need for intubation after birth, and chronic ventilator support. Similar to CDH, further studies may prove that it prognosticates for ECMO use and for mortality. Detailed prenatal counseling and realistic expectations can be provided.

For infants that do not survive, lung-volume-to-body-weight ratios have been established for term and preterm infants [10]. Assessment of lung growth is a critical component of perinatal autopsy. One single series review reports lung biopsy or autopsy pathologic diagnosis of pulmonary hypoplasia or pulmonary hypertension in five omphalocele cases but does not expand on the precise histology details [7].

Fetal magnetic resonance lung volume curves and pathologic lung-volume-to-body-weight ratios for gestational age exist, but clinical-pathologic correlation studies are needed to further characterize pulmonary hypoplasia in infants with omphaloceles.

## **4. The contribution of major anomalies**

Infants with major anomalies and omphaloceles have a longer duration of mechanical ventilation, hospital stay and a need for oxygen at 30 days of life. In a single-institution series of 82 live-born infants, 26% had chromosomal and 30% had major associated anomalies. None of the 19 live-born infants with an isolated defect died. Mortality, however, was 41% and 17% for those with major and minor anomalies, respectively [22].

The presence of associated anomalies is a strong predictor of morbidity and mortality, and anomalies are also linked to respiratory status [5, 16, 23].

Beckwith-Wiedemann syndrome is characterized by omphalocele, macroglossia, macrosomia, hypoglycemia, and embryonic tumors. It is a growth disorder due to dysregulation of the growth regulatory gene on chromosome 11p15 [23]. The presence of hypoglycemia in the perinatal period should alert the clinician to the possibility of Beckwith-Wiedemann syn‐ drome.

The finding of omphalocele on a prenatal ultrasound should prompt a search for associated anomalies and possible further prenatal testing. In a large prenatal study of 445 fetuses with omphalocele, diagnosed in the first trimester, only 55 were live born. Over 85% died in utero due to the presence of fatal chromosomal anomalies [2, 3].

The presence of omphalocele indicates an increased risk of aneuploidy. In a recent first trimester study, fetuses with an omphalocele were found to carry a chromosomal abnormality in 55% of cases [16]. The most frequent abnormal karyotypes in omphalocele infants are Trisomy 18 and 13 [24]. Both have almost 100% incidence of congenital heart defects, including ventricular septal defect, atrial septal defect, and double outlet right ventricle. Infants with omphaloceles, in the setting of Trisomy 13 or 18 and a congenital heart defect, tend to have severe hemodynamic compromise.

In the setting of omphalocele and major anomalies, the cardiopulmonary support provided by the clinician is intensified [25].

Congenital diaphragmatic hernia is sporadically reported in conjunction with an omphalocele. Careful review of fetal MRI of the diaphragm may identify congenital diaphragmatic hernia. Conflicting reports exist, but generally pulmonary hypertension is profound and the outcome is poor [7, 26]. Elevated hemidiaphragms, diaphragmatic eventration, and congenital dia‐ phragmatic hernia have been described in infants with giant omphaloceles, and could contribute to impaired lung development and postnatal distress [8, 11, 27].

## **5. Pulmonary hypertension**

Similar to CDH and CLM, this calculation reflects pulmonary hypoplasia and allows clinicians to prepare for increased respiratory distress, a need for intubation after birth, and chronic ventilator support. Similar to CDH, further studies may prove that it prognosticates for ECMO use and for mortality. Detailed prenatal counseling and realistic expectations can be provided.

For infants that do not survive, lung-volume-to-body-weight ratios have been established for term and preterm infants [10]. Assessment of lung growth is a critical component of perinatal autopsy. One single series review reports lung biopsy or autopsy pathologic diagnosis of pulmonary hypoplasia or pulmonary hypertension in five omphalocele cases but does not

Fetal magnetic resonance lung volume curves and pathologic lung-volume-to-body-weight ratios for gestational age exist, but clinical-pathologic correlation studies are needed to further

Infants with major anomalies and omphaloceles have a longer duration of mechanical ventilation, hospital stay and a need for oxygen at 30 days of life. In a single-institution series of 82 live-born infants, 26% had chromosomal and 30% had major associated anomalies. None of the 19 live-born infants with an isolated defect died. Mortality, however, was 41% and 17%

The presence of associated anomalies is a strong predictor of morbidity and mortality, and

Beckwith-Wiedemann syndrome is characterized by omphalocele, macroglossia, macrosomia, hypoglycemia, and embryonic tumors. It is a growth disorder due to dysregulation of the growth regulatory gene on chromosome 11p15 [23]. The presence of hypoglycemia in the perinatal period should alert the clinician to the possibility of Beckwith-Wiedemann syn‐

The finding of omphalocele on a prenatal ultrasound should prompt a search for associated anomalies and possible further prenatal testing. In a large prenatal study of 445 fetuses with omphalocele, diagnosed in the first trimester, only 55 were live born. Over 85% died in utero

The presence of omphalocele indicates an increased risk of aneuploidy. In a recent first trimester study, fetuses with an omphalocele were found to carry a chromosomal abnormality in 55% of cases [16]. The most frequent abnormal karyotypes in omphalocele infants are Trisomy 18 and 13 [24]. Both have almost 100% incidence of congenital heart defects, including ventricular septal defect, atrial septal defect, and double outlet right ventricle. Infants with omphaloceles, in the setting of Trisomy 13 or 18 and a congenital heart defect, tend to have

expand on the precise histology details [7].

30 Respiratory Management of Newborns

**4. The contribution of major anomalies**

characterize pulmonary hypoplasia in infants with omphaloceles.

for those with major and minor anomalies, respectively [22].

anomalies are also linked to respiratory status [5, 16, 23].

due to the presence of fatal chromosomal anomalies [2, 3].

severe hemodynamic compromise.

drome.

Previously, nonspecific respiratory insufficiency at birth was reported as an independent predictor of mortality for infants with omphaloceles. Older reports do not distinguish between pulmonary hypertension and pulmonary hypoplasia in their contribution to ventilation difficulties.

Pulmonary hypertension is now established as an independent predictor of mortality in infants with omphaloceles [28]. One recent series found that mortality was highest for live-born infants with omphaloceles diagnosed with pulmonary hypertension (45%), considerably higher than mortality in a cohort of infants with omphaloceles alone (18%) [29]. The contribution of pulmonary hypertension to respiratory insufficiency was previously unappreciated [28].

Pulmonary hypertension is diagnosed using echocardiography performed after the second day of life. Changes in the transitional circulation on the first day of life preclude evaluation for pulmonary hypertension by echocardiography. Directionality of flow through the ductus arteriosus is not considered in the diagnosis of pulmonary hypertension on the first day of life.

Pulmonary hypertension is defined on echocardiography as flattening of the interventricular septum during systole and/or a tricuspid regurgitant jet (TR) with an estimated right ventric‐ ular pressure greater than 40 mmHg when observed in the setting of hypoxemia [28, 30]. Qualitative measures of right-sided stress, as determined by the cardiologist interpreting the study, contribute to the assessment. These are right ventricular dilation, right atrial enlarge‐ ment, right ventricular hypertrophy, septal flattening, and pulmonary artery dilation [28, 30, 31].

The incidence of pulmonary hypertension is reported in 37 to 55% of infants with giant omphaloceles. It is more prevalent in infants with additional anomalies [28, 31]. The explana‐ tion, whether structural, oxygen tension related, genetic, or some other cause, remains unknown.

Pulmonary hypertension correlates to endpoints of pulmonary insufficiency, including duration of mechanical ventilation, requirement for high-frequency oscillator ventilation, need for tracheostomy, and reliance on oxygen at the time of discharge from neonatal intensive care unit [31].

Conflicting reports exist regarding the prognosis of infants with giant omphaloceles. Some have mild respiratory distress, achieve early feeding and undergo delayed fascial closure with good results [28]. In contrast, others report a high mortality rate in giant omphalocele infants, relating to the predominance of respiratory insufficiency and pulmonary hypertension.

Several retrospective studies suggest that there may be a direct relationship between giant defects and abnormal pulmonary vascular tone. Clinicians should not focus on the defect diameter, but recognize that respiratory insufficiency and pulmonary hypertension are the prognosticators to identify [8, 18, 32].

A recent multicenter retrospective review illustrates the distribution of respiratory insuffi‐ ciency and pulmonary hypertension in 51 infants with omphalocele (**Figure 1**). All 51 had echocardiography performed between the day of life 2 and 7 [28].

Sixteen infants (31%) had no pulmonary hypertension and no respiratory insufficiency at birth. Of these, 15 survived (94%) and 1 died (6%).

Of the 51 infants (55%), 28 had pulmonary hypertension, and of these, 13 had respiratory insufficiency (46%) while 15 did not (54%).

Of the 51 (39%), 20 infants had respiratory insufficiency at birth without detectable pulmonary hypertension. Six of twenty (30%) were premature infants with a mean gestational age of 31.7 weeks.

Ninety-two percent of mortalities in the cohort were distributed among the infants with pulmonary hypertension, with or without respiratory failure, or respiratory failure without pulmonary hypertension. Of 38 survivors, one that initially presented with respiratory insufficiency, without pulmonary hypertension, progressed to chronic lung disease and required a tracheostomy and a long-term ventilator support. Of the 15 infants with isolated

**Figure 1.** The distribution of respiratory failure and pulmonary hypertension in 51 infants with omphaloceles.

pulmonary hypertension and no evidence of respiratory insufficiency, 13 survived (87%), and none required long-term ventilation (**Figure 1**).

Conflicting reports exist regarding the prognosis of infants with giant omphaloceles. Some have mild respiratory distress, achieve early feeding and undergo delayed fascial closure with good results [28]. In contrast, others report a high mortality rate in giant omphalocele infants, relating to the predominance of respiratory insufficiency and pulmonary hypertension.

Several retrospective studies suggest that there may be a direct relationship between giant defects and abnormal pulmonary vascular tone. Clinicians should not focus on the defect diameter, but recognize that respiratory insufficiency and pulmonary hypertension are the

A recent multicenter retrospective review illustrates the distribution of respiratory insuffi‐ ciency and pulmonary hypertension in 51 infants with omphalocele (**Figure 1**). All 51 had

Sixteen infants (31%) had no pulmonary hypertension and no respiratory insufficiency at birth.

Of the 51 infants (55%), 28 had pulmonary hypertension, and of these, 13 had respiratory

Of the 51 (39%), 20 infants had respiratory insufficiency at birth without detectable pulmonary hypertension. Six of twenty (30%) were premature infants with a mean gestational age of 31.7

Ninety-two percent of mortalities in the cohort were distributed among the infants with pulmonary hypertension, with or without respiratory failure, or respiratory failure without pulmonary hypertension. Of 38 survivors, one that initially presented with respiratory insufficiency, without pulmonary hypertension, progressed to chronic lung disease and required a tracheostomy and a long-term ventilator support. Of the 15 infants with isolated

**Figure 1.** The distribution of respiratory failure and pulmonary hypertension in 51 infants with omphaloceles.

echocardiography performed between the day of life 2 and 7 [28].

prognosticators to identify [8, 18, 32].

32 Respiratory Management of Newborns

Of these, 15 survived (94%) and 1 died (6%).

insufficiency (46%) while 15 did not (54%).

weeks.

Giant omphalocele defects containing 75% liver were closely associated with mortality. The distribution of 17 giant defects is illustrated among the cohort in **Figure 1**. Eight of seventeen (47%) died, and the eight deaths with giant defects were all distributed in the nine infant deaths that had a combination of pulmonary hypertension and respiratory failure at birth (89%). The distribution of the remaining giant defects is illustrated among the survivors (**Figure 1**) [28].

Logistic regression analysis further revealed that both respiratory insufficiency at birth (OR: 14.8; 95% CI: 2.5–85.0) and pulmonary hypertension diagnosed between days 2 and 7 of life (OR: 6.4; 95% CI: 1.1–39.0) were independently associated with mortality in infants with omphaloceles. This is a new and previously unappreciated finding.

A clinical care strategy that screens for pulmonary hypertension in omphalocele infants is recommended. Echocardiography is best performed between the second and seventh day of life to avoid examination during transitional circulation. Echocardiography should be performed at regular intervals until resolution or stabilization of pulmonary hypertension is demonstrated [28, 30].

The aims of pharmacotherapy for pulmonary hypertension are pulmonary vasodilation, restoration of normal endothelial function, and reversal of remodeling of the pulmonary vasculature. All of these therapies reduce right ventricular afterload and prevent right ventricular failure. Pulmonary vasodilation is needed acutely for pulmonary hypertension, but long-term therapy may focus on vascular remodeling. The main therapies for pulmonary hypertension emphasize the nitric oxide, prostacyclin, and endothelin pathways [33].

There are sporadic reports of the use of ventilator support with inhaled nitric oxide to treat omphalocele infants with pulmonary hypertension. However, detailed reports of lung function measurements before and after trials of inhaled nitric oxide that establish vascular reactivity are few [25]. The phosphodiesterase inhibitor and vasodilator, sildenafil, is admin‐ istered with success in sporadic series.

After nitric oxide, sildenafil is considered the next-line therapy for pulmonary hypertension in infants, irrespective of etiology [31, 34]. Sildenafil generally improves the oxygenation index with minimal adverse effects in infants with pulmonary hypertension. Despite sildenafil, however, abnormal vascular tone does not necessarily resolve. One-quarter of giant ompha‐ locele infants may require long-term vasodilator therapy with sildenafil [31].

We report one case of giant omphalocele treated with sildenafil and Bosentan. Echo performed at age 4 years shows that the pulmonary hypertension has completely resolved. Bosentan is an oral endothelin receptor antagonist that inhibits vascular remodeling and muscular thickening. Endothelin-1 is believed to play a role in the pathogenesis of neonatal pulmonary hypertension, and endothelin blockade augments pulmonary vasodilation in the perinatal lung. Several reports have shown that Bosentan provides benefit in the treatment of pulmonary hypertension in infants [33].

Selected fetuses may benefit from a maternal hyperoxia study prenatally to predict who will be at risk for elevated pulmonary vascular resistance and pulmonary hypertension, similar to prenatal evaluation in congenital diaphragmatic hernia [25, 35, 36].

The biology of neonatal pulmonary hypertension is linked to lung vascular growth modified by prenatal and early postnatal factors. The use of medical therapy to modify pulmonary hypertension in omphalocele infants is an important area of future study [37].

## **6. Congenital heart defects**

The anterior abdominal wall develops between weeks 3 and 10 of fetal development. The process involves folding of the embryonic disk in cranio-caudal and lateral directions. By week 6 of fetal development, the elongated midgut herniates into the base of the umbilical cord due to lack of space in the abdominal cavity. By the tenth week, it rotates and returns to the abdomen. During this period, the cardiac tubes, which lie on the ventral surface of the embryo, are incorporated into the chest by the lateral folds. Errors in these critical steps of fetal development result in simultaneous anterior abdominal wall defects, such as omphalocele, and structural cardiac defects [25].

In general, a single- or multiinstitutional series of live-born infants with omphaloceles report a 30% incidence of structural congenital heart defects. Neonates with patent ductus arteriosus or patent foramen ovale are not considered to have a congenital heart defect.

A single-center retrospective series found that of 22 live-born omphalocele infants, 7 had evidence of a structural congenital heart defect, 4 of which developed pulmonary hyperten‐ sion, and 1 of the 4 also had a dysplastic tricuspid valve. Only one infant required a surgical repair, and that infant presented with coarctation of the aorta [25]. The incidence of structural cardiac defects was lower than expected, and this was attributed to the low incidence of abnormal karyotypes.

Another recent multicenter series reports a congenital heart defect incidence in omphalocele infants of 30%, but all were nonductal-dependent lesions without hemodynamic compromise. None had cardiac failure [28].

Although structural cardiac defects should be specifically sought by echo in the first week of life, the influence of congenital heart defects on the outcome for omphalocele infants may be lower than expected, in particular if the cohort has normal karyotypes.

Although clinicians previously evaluated for congenital heart defects, they did not evaluate for pulmonary hypertension. Recent reports clarify that pulmonary hypertension likely has a greater influence on the outcome and mortality in omphalocele infants than congenital heart defects, unless Trisomy 13 or 18 is diagnosed.

In the setting of Trisomy 13 or 18, the incidence of congenital heart defects is over 90%. The most common defects are ventricular septal defect, atrial septal defect, and double outlet right ventricle.

The congenital heart defects of these chromosomal anomalies tend to present with hemody‐ namic compromise [25, 28, 38]. The establishment of regional and national databases for omphalocele would enhance the statistical understanding of the true incidence of congenital heart defects and hemodynamic compromise in omphalocele infants as few detailed reports with large sample size exist.

## **7. Respiratory insufficiency and assisted ventilation**

Assisted ventilation may be necessary in neonates with omphalocele due to respiratory insufficiency from pulmonary hypoplasia, increased abdominal pressure following surgical repair, diaphragm dysfunction, and pulmonary hypertension [39]. The need for assisted ventilation may occur at delivery or may be confined to the immediate postoperative period related to increased intraabdominal pressure and upward displacement of the diaphragm following closure.

#### **7.1. Goals of assisted ventilation**

Selected fetuses may benefit from a maternal hyperoxia study prenatally to predict who will be at risk for elevated pulmonary vascular resistance and pulmonary hypertension, similar to

The biology of neonatal pulmonary hypertension is linked to lung vascular growth modified by prenatal and early postnatal factors. The use of medical therapy to modify pulmonary

The anterior abdominal wall develops between weeks 3 and 10 of fetal development. The process involves folding of the embryonic disk in cranio-caudal and lateral directions. By week 6 of fetal development, the elongated midgut herniates into the base of the umbilical cord due to lack of space in the abdominal cavity. By the tenth week, it rotates and returns to the abdomen. During this period, the cardiac tubes, which lie on the ventral surface of the embryo, are incorporated into the chest by the lateral folds. Errors in these critical steps of fetal development result in simultaneous anterior abdominal wall defects, such as omphalocele,

In general, a single- or multiinstitutional series of live-born infants with omphaloceles report a 30% incidence of structural congenital heart defects. Neonates with patent ductus arteriosus

A single-center retrospective series found that of 22 live-born omphalocele infants, 7 had evidence of a structural congenital heart defect, 4 of which developed pulmonary hyperten‐ sion, and 1 of the 4 also had a dysplastic tricuspid valve. Only one infant required a surgical repair, and that infant presented with coarctation of the aorta [25]. The incidence of structural cardiac defects was lower than expected, and this was attributed to the low incidence of

Another recent multicenter series reports a congenital heart defect incidence in omphalocele infants of 30%, but all were nonductal-dependent lesions without hemodynamic compromise.

Although structural cardiac defects should be specifically sought by echo in the first week of life, the influence of congenital heart defects on the outcome for omphalocele infants may be

Although clinicians previously evaluated for congenital heart defects, they did not evaluate for pulmonary hypertension. Recent reports clarify that pulmonary hypertension likely has a greater influence on the outcome and mortality in omphalocele infants than congenital heart

In the setting of Trisomy 13 or 18, the incidence of congenital heart defects is over 90%. The most common defects are ventricular septal defect, atrial septal defect, and double outlet right

or patent foramen ovale are not considered to have a congenital heart defect.

lower than expected, in particular if the cohort has normal karyotypes.

prenatal evaluation in congenital diaphragmatic hernia [25, 35, 36].

**6. Congenital heart defects**

34 Respiratory Management of Newborns

and structural cardiac defects [25].

abnormal karyotypes.

ventricle.

None had cardiac failure [28].

defects, unless Trisomy 13 or 18 is diagnosed.

hypertension in omphalocele infants is an important area of future study [37].

The goal of assisted ventilation in neonates with respiratory insufficiency due to omphalocele is to achieve adequate functional residual capacity to facilitate gas exchange. Assisted venti‐ lation should be applied to maintain adequate lung volume with even distribution of tidal volume to avoid trauma from atelectasis and lung injury. If lungs with partial atelectasis are ventilated, the tidal volume entering only the open alveoli will lead to overexpansion of the relatively healthy portion of the lung with subsequent trauma due to overexpansion.

Additionally, atelectasis leads to vascular protein leak with increased surfactant inactivation and release of inflammatory mediators. Maintaining adequate lung volume is achieved by applying adequate positive end expiratory pressure (PEEP). There is no single optimal PEEP, and the level must be tailored to the degree of lung injury. For infants with healthy lungs and normal lung compliance, PEEP of 3–4 cm H2O may be appropriate. Excessive PEEP may lead to overexpansion of normal lungs with circulatory impairment and elevated cerebral venous pressure. However, poorly compliant lungs with atelectasis may transiently require higher PEEP, as high as 8–10 cm H20 or more, to achieve adequate alveolar recruitment and optimize ventilation/perfusion ratios [40].

For small omphaloceles, if primary abdominal closure has been accomplished, the majority of neonates will require mechanical ventilation for a few days postoperatively. During this time, the abdominal wall and bowel wall edema will improve, and the intraabdominal pressure will decrease.

The elective, routine use of mechanical ventilation to ensure primary closure in every instance is unwarranted. Short-term ventilator support, however, has been a welcomed adjunct to postoperative care and certainly has improved the outlook for these infants [41].

#### **7.2. Noninvasive ventilation**

Little information exists regarding the use of continuous positive airway pressure (CPAP) or positive end expiratory pressure (PEEP) in stabilizing the lungs of infants with omphaloceles. Positive end expiratory pressure has been used in premature infants to minimize the effect of excessively compliant chest wall and surfactant deficiency by stabilizing alveoli during the expiratory phase, and has been shown to help establish functional residual capacity.

Traditional management in neonates with omphalocele and respiratory insufficiency involves intubation and mechanical ventilation in the delivery room to presumably avoid further distention of bowel from air swallowing. However, nasal CPAP and/or nasal intermittent positive pressure ventilation may be a preferable approach to improve inadequate respiratory effort in these neonates, while avoiding the complications associated with endotracheal intubation [42].

The noninvasive approach offers the benefit of avoiding an endotracheal tube; therefore, reducing the incidence of ventilator-associated pneumonia and avoiding the contribution of postnatal inflammatory response to the development of bronchopulmonary dysplasia. Noninvasive ventilation reduces iatrogenic lung injury.

#### **7.3. Conventional mechanical ventilation**

Several modes of mechanical ventilation have been applied to neonates with omphalocele, but there is little evidence to guide clinicians in selecting the best method. Historically, pressurecontrolled ventilation is the standard mode of ventilation in neonates with respiratory failure because of its wide availability, simplicity, ability to ventilate despite large endotracheal tube leak, and improved intrapulmonary gas distribution. However, pressure-controlled ventila‐ tion is limited, in that tidal volume varies with changes in lung compliance.

A rapid improvement in compliance may occur in the immediate postnatal period as a result of resorption of lung fluid, recruitment of optimal lung volume, and surfactant replacement therapy, leading to hyperventilation and trauma from excessive lung hyperexpansion [40].

Insufficient tidal volume may develop because of decreasing lung compliance, increasing airway resistance, airway obstruction, air trapping, and/or decreased spontaneous respiratory effort. Inadequate lung volume leads to hypercapnia, increased work of breathing and oxygen consumption, agitation, fatigue and atelectasis/atelectrauma. Low tidal volume leads to inefficient gas exchange due to increased dead space: tidal-volume ratio. Mechanical ventila‐ tion goals should include weaning toward extubation, as well as weaning supplemental FiO2, in order to avoid oxygen toxicity that may contribute to chronic lung disease.

#### **7.4. High-frequency ventilation**

In selected infants with respiratory failure due to pulmonary hypoplasia and/or severe pulmonary hypertension, high-frequency ventilation may optimize lung inflation and improve gas exchange. High-frequency ventilation is beneficial as it reduces pressure and volume swings transmitted to the periphery of the lungs, and promotes gentle ventilation. For optimal effectiveness, alveoli must be recruited and stabilized with the lowest possible mean airway pressure.

**7.2. Noninvasive ventilation**

36 Respiratory Management of Newborns

intubation [42].

Little information exists regarding the use of continuous positive airway pressure (CPAP) or positive end expiratory pressure (PEEP) in stabilizing the lungs of infants with omphaloceles. Positive end expiratory pressure has been used in premature infants to minimize the effect of excessively compliant chest wall and surfactant deficiency by stabilizing alveoli during the

Traditional management in neonates with omphalocele and respiratory insufficiency involves intubation and mechanical ventilation in the delivery room to presumably avoid further distention of bowel from air swallowing. However, nasal CPAP and/or nasal intermittent positive pressure ventilation may be a preferable approach to improve inadequate respiratory effort in these neonates, while avoiding the complications associated with endotracheal

The noninvasive approach offers the benefit of avoiding an endotracheal tube; therefore, reducing the incidence of ventilator-associated pneumonia and avoiding the contribution of postnatal inflammatory response to the development of bronchopulmonary dysplasia.

Several modes of mechanical ventilation have been applied to neonates with omphalocele, but there is little evidence to guide clinicians in selecting the best method. Historically, pressurecontrolled ventilation is the standard mode of ventilation in neonates with respiratory failure because of its wide availability, simplicity, ability to ventilate despite large endotracheal tube leak, and improved intrapulmonary gas distribution. However, pressure-controlled ventila‐

A rapid improvement in compliance may occur in the immediate postnatal period as a result of resorption of lung fluid, recruitment of optimal lung volume, and surfactant replacement therapy, leading to hyperventilation and trauma from excessive lung hyperexpansion [40].

Insufficient tidal volume may develop because of decreasing lung compliance, increasing airway resistance, airway obstruction, air trapping, and/or decreased spontaneous respiratory effort. Inadequate lung volume leads to hypercapnia, increased work of breathing and oxygen consumption, agitation, fatigue and atelectasis/atelectrauma. Low tidal volume leads to inefficient gas exchange due to increased dead space: tidal-volume ratio. Mechanical ventila‐ tion goals should include weaning toward extubation, as well as weaning supplemental FiO2,

In selected infants with respiratory failure due to pulmonary hypoplasia and/or severe pulmonary hypertension, high-frequency ventilation may optimize lung inflation and improve gas exchange. High-frequency ventilation is beneficial as it reduces pressure and volume swings transmitted to the periphery of the lungs, and promotes gentle ventilation. For

tion is limited, in that tidal volume varies with changes in lung compliance.

in order to avoid oxygen toxicity that may contribute to chronic lung disease.

Noninvasive ventilation reduces iatrogenic lung injury.

**7.3. Conventional mechanical ventilation**

**7.4. High-frequency ventilation**

expiratory phase, and has been shown to help establish functional residual capacity.

There is little information in the literature describing the effectiveness of high-frequency ventilation in neonates with omphalocele. In a large single-center series of giant omphalocele infants, mechanical ventilation maintains preductal oxygen saturation above 85% and highfrequency oscillatory ventilation is reserved for patients with refractory hypercapnia [41].

One report examines the use of high-frequency ventilation in 15 omphalocele infants after surgical closure. Of 15 infants, 11 had not required ventilation and were breathing room air prior to operation. High-frequency ventilation is reported as required in six infants (61%) within the first week in the intensive care unit after omphalocele closure. The remainder were managed with conventional ventilation. In half of the 15 infants, lung expansion on chest radiograph was reported at 50%.

The average mean airway pressure at days 5–7 for both the conventional ventilation group and the high-frequency group was 14 mmHg ± 3.0. Weaning from ventilation was achieved on day 7 in only five of the omphalocele infants. Six required ventilation until day 28. Four infants required tracheostomy and prolonged respiratory support between 330 and 1065 days [38]. Prolonged duration of mechanical ventilation and use of parenteral nutrition during this time period likely also contribute to an increased risk of infection.

Primary closure was the procedure of choice in this series. Despite the use of high-frequency ventilation, this series reports a slightly lower survival rate of 73%, compared to the studies with an emphasis on delayed closure that report survival rates of 80% or higher. They note that tension was described by the surgeon in three closures and may have contributed to postoperative difficulties. They note closure of the abdominal wall defect compromised pulmonary mechanics when increased intraabdominal pressure inhibited diaphragmatic movements as the viscera was reduced [38].

This study supports the existence of a degree of pulmonary hypoplasia and decreased pulmonary reserve in omphalocele infants that could only be overcome to a degree by highfrequency ventilation in some but not all of the infants that underwent early closure. It supports the use of delayed closure techniques and careful evaluation of abdominal-visceral dispro‐ portion and cardiopulmonary status prior to proceeding with operation [38].

## **8. Extra-corporeal membrane oxygenation (ECMO)**

Despite improvements in the management of respiratory insufficiency and pulmonary hypertension in infants, a number of infants with inadequate gas exchange are treated with extra-corporeal membrane oxygenation (ECMO). This includes infants with omphaloceles.

The authors retrospectively analyzed the Extra-corporeal Life Support Organization (ELSO, Ann Arbor, MI, USA) database between 1992 and 2015 for extra-corporeal membrane oxy‐ genator (ECMO) use and omphalocele. ELSO membership consists of many major medical centers worldwide, with the capability of placing infants on ECMO. This database would capture the majority of infants with omphaloceles, managed with ECMO, during the time period and provide the most of the information about the use of ECMO in these infants. The first infant with an omphalocele was placed on ECMO in 2011.

The specific diagnoses for respiratory insufficiency listed in the database are pulmonary hypertension, congenital heart defects, congenital diaphragmatic hernia, and sepsis. The recorded diagnoses for respiratory insufficiency in the 11 infants were isolated pulmonary hypertension in three; congenital heart defect and pulmonary hypertension in five (one of the five also had capillary alveolar dysplasia); congenital diaphragmatic hernia, congenital heart defect, sepsis, and pulmonary hypertension in one; and congenital diaphragmatic hernia and pulmonary hypertension in two infants.

The six congenital heart defects were double outlet right ventricle in two, Tetralogy of Fallot in one, ventricular septal defect in one, cor triatriatum in one, and aortic atresia/stenosis in one.

**Table 2** presents the demographic details and outcomes of 11 infants with omphaloceles placed on ECMO between 2011 and 2015.

**Table 2.** Omphalocele infants that underwent ECMO (2011–2015).

This is a small but significant series as it provides the only data available at present for omphalocele infants and the use of ECMO. The incidence of abnormal karyotypes is not reported with the database, so any association with Trisomy 13 or 18 is unknown.

For infants with omphaloceles that underwent ECMO, between 2011 and 2015 and reported in the ELSO database, the overall mortality was 80%. This high mortality rate contrasts to the reports from a large multicenter series of infants that underwent ECMO for pulmonary hypertension and other conditions such as congenital diaphragmatic hernia between 2000 and 2010, where the mortality rate is 20% or better. These data support the need to better under‐ stand the underlying pathophysiology of pulmonary hypertension, so therapy can target its causes in omphalocele infants. There is overlap in the diagnoses of respiratory insufficiency in almost all cases of omphalocele placed on ECMO. Only a large study with multivariate analysis could determine the contribution of each diagnosis to respiratory failure and mortality in omphalocele infants.

One term infant with omphalocele, and respiratory insufficiency attributable to congenital heart defect and pulmonary hypertension, underwent lung biopsy after 10 days of ECMO support. The lung biopsy revealed capillary alveolar dysplasia. Extra-corporeal membrane oxygenation was withdrawn due to the fatal prognosis.

This solitary report raises questions about the etiology of persistent pulmonary hypertension in some omphalocele infants. More autopsy studies and published reports after examination of omphalocele infant lungs may expand the understanding of the contribution of this disorder to pulmonary hypertension and mortality.

Clinically, capillary alveolar dysplasia cannot be distinguished from other syndromes that cause pulmonary hypertension. Histologically, it is characterized by paucity of capillaries adjacent to alveolar epithelium, immature alveolar development, and muscularization of arterioles. The distribution can be diffuse or patchy. The etiology and incidence of capillary alveolar dysplasia are unknown [43].

## **9. Surgical considerations**

centers worldwide, with the capability of placing infants on ECMO. This database would capture the majority of infants with omphaloceles, managed with ECMO, during the time period and provide the most of the information about the use of ECMO in these infants. The

The specific diagnoses for respiratory insufficiency listed in the database are pulmonary hypertension, congenital heart defects, congenital diaphragmatic hernia, and sepsis. The recorded diagnoses for respiratory insufficiency in the 11 infants were isolated pulmonary hypertension in three; congenital heart defect and pulmonary hypertension in five (one of the five also had capillary alveolar dysplasia); congenital diaphragmatic hernia, congenital heart defect, sepsis, and pulmonary hypertension in one; and congenital diaphragmatic hernia and

The six congenital heart defects were double outlet right ventricle in two, Tetralogy of Fallot in one, ventricular septal defect in one, cor triatriatum in one, and aortic atresia/stenosis in one.

**Table 2** presents the demographic details and outcomes of 11 infants with omphaloceles placed

) data are expressed in median (range).

This is a small but significant series as it provides the only data available at present for omphalocele infants and the use of ECMO. The incidence of abnormal karyotypes is not

For infants with omphaloceles that underwent ECMO, between 2011 and 2015 and reported in the ELSO database, the overall mortality was 80%. This high mortality rate contrasts to the reports from a large multicenter series of infants that underwent ECMO for pulmonary

reported with the database, so any association with Trisomy 13 or 18 is unknown.

**Omphalocele** *N* **= 11**

first infant with an omphalocele was placed on ECMO in 2011.

First recorded ECMO run 2011 ECMO after day of life 3 8 (73%) Gender (male) 7 (64%) Weight at ECMO (kg)a 3.27 (2.5–10) Age at ECMO (days)a 10 (0–351) Run length (hours)a 193 (11–589) A diagnosis of PHN 11 (100%) Veno-arterial ECMO 10 (91%) Discontinued from ECMO alive 7 (64%) Discharged from hospital alive 2 (18%)

pulmonary hypertension in two infants.

38 Respiratory Management of Newborns

on ECMO between 2011 and 2015.

Data are expressed in number (%) except with (a

**Table 2.** Omphalocele infants that underwent ECMO (2011–2015).

The aim of surgical management in infants with omphaloceles is to avoid an abrupt increase in the abdominal pressure that may impair ventilation. An omphalocele which is less than 4 cm in size may be suitable for primary repair after cardiopulmonary stabilization and assess‐ ment of anomalies. In contrast, if a giant omphalocele is closed too early, the intraabdominal volume may be insufficient to contain the organs [4, 5].

Immediate postoperative complications are compromise of venous return from a sudden increase in intra-abdominal pressure and cardiopulmonary instability from decreased diaphragmatic excursion. The result is abdominal compartment syndrome (ACS) [38, 39].

Compartment syndrome due to increased intraabdominal pressure is a serious complication after a difficult omphalocele reduction. Early series report a 12% incidence of complications, including acute hepatic congestion, renal failure, and bowel infarction [5, 6].

Before the impact of viscero-abdominal disproportion (VAD) and abdominal compartment syndrome was understood, surgeons placed emphasis on operative closure. Between 1980 and 1995, in a series of 30 operative closures, about half were small defects and were closed primarily without complications [44].

The remainder were giant omphaloceles. Three underwent skin closure due to visceroabdominal disproportion. Thirteen underwent silo placement and were closed between 11 and

**Table 3.** Operative complications [44].

137 days. There were 14 serious complications in 13 infants. All were due to initial tight closure, and all were opened postoperatively. There was one postoperative death (**Table 3**).

No randomized studies show that intraabdominal pressure monitoring is beneficial, and therefore it is not used to guide closure in the operating room, but may have a role in the postoperative period. Continuous bladder pressure monitoring in the postoperative period does not prevent necrotizing enterocolitis, but maintaining abdominal pressure below 20 mmHg prevents renal failure [45].

Various closure techniques for giant omphalocele exist, including alloderm patch, vacuumassisted closure, tissue expanders, silos, and other types of mesh materials [46, 47]. If the sac is intact, application of topical agents and dressing changes for initial nonoperative manage‐ ment of a giant omphalocele is recommended. This technique transitions to delayed closure [26]. Tension and intraabdominal compression increase morbidity and must be avoided during closure. If tension exists, then a silo or mesh must be used for coverage [38].

In two recent series, infants with giant omphaloceles underwent treatment of the sac with topical agents and delayed closure. The median age of repair was 10 months (range: 3.4–23.6 months) in one series and 215 days in the other. No repairs were opened postoperatively [4, 22]. Six-month survival was 80% in both the series, despite the fact that half of the delayed closure infants in one series met the criteria for pulmonary hypoplasia on fetal magnetic resonance imaging [22].

A recent series of 16 infants with giant omphaloceles achieved discharge and returned for delayed closure during an elective admission at a median of 14 months (range: 2–28 months). The median length of hospital stay for this elective admission was 4 days (range: 2–21 days). One of sixteen (6%) required unexpected prolonged ventilation and stayed in hospital for 21 days. Four (25%) required mesh as viscero-abdominal disproportion had not resolved [26].

When compared to the reports obtained from previous decades, surgeons wait 7–24 months longer before attempting closure of a giant omphalocele. Although no comparative studies exist, the concept of giant omphalocele closure has evolved over the last two decades [38, 39].

Most surgeons promote application of topical agents to the sac, followed by delayed closure. This approach allows improved respiratory status, fewer complications, and better outcomes [1, 4, 22, 26]. The emphasis on closure has been replaced by a better appreciation of visceroabdominal disproportion, abdominal compartment syndrome, and the connection between stable cardiopulmonary status and survival.

Clinicians should be aware, however, that even if closure succeeds, a 40–50% reduction in respiratory system compliance on the first and second postoperative days after closure of abdominal wall defects has been demonstrated, as well as a 38% reduction in forced vital capacity.

Mechanical ventilation, including high-frequency ventilation, may be required after delayed omphalocele closure [9, 26, 27].

### **9.1. Technique of delayed repair**

137 days. There were 14 serious complications in 13 infants. All were due to initial tight closure,

No randomized studies show that intraabdominal pressure monitoring is beneficial, and therefore it is not used to guide closure in the operating room, but may have a role in the postoperative period. Continuous bladder pressure monitoring in the postoperative period does not prevent necrotizing enterocolitis, but maintaining abdominal pressure below 20

Various closure techniques for giant omphalocele exist, including alloderm patch, vacuumassisted closure, tissue expanders, silos, and other types of mesh materials [46, 47]. If the sac is intact, application of topical agents and dressing changes for initial nonoperative manage‐ ment of a giant omphalocele is recommended. This technique transitions to delayed closure [26]. Tension and intraabdominal compression increase morbidity and must be avoided during

In two recent series, infants with giant omphaloceles underwent treatment of the sac with topical agents and delayed closure. The median age of repair was 10 months (range: 3.4–23.6 months) in one series and 215 days in the other. No repairs were opened postoperatively [4, 22]. Six-month survival was 80% in both the series, despite the fact that half of the delayed closure infants in one series met the criteria for pulmonary hypoplasia on fetal magnetic

A recent series of 16 infants with giant omphaloceles achieved discharge and returned for delayed closure during an elective admission at a median of 14 months (range: 2–28 months). The median length of hospital stay for this elective admission was 4 days (range: 2–21 days). One of sixteen (6%) required unexpected prolonged ventilation and stayed in hospital for 21 days. Four (25%) required mesh as viscero-abdominal disproportion had not resolved [26]. When compared to the reports obtained from previous decades, surgeons wait 7–24 months longer before attempting closure of a giant omphalocele. Although no comparative studies exist, the concept of giant omphalocele closure has evolved over the last two decades [38, 39]. Most surgeons promote application of topical agents to the sac, followed by delayed closure. This approach allows improved respiratory status, fewer complications, and better outcomes

and all were opened postoperatively. There was one postoperative death (**Table 3**).

**Complication** *N* **(%)** Wound dehiscence 7 (24%) Gastroesophageal reflux 5 (17%) Hepatic hematoma 3 (10%) Hepatic congestion 2 (6%) Enterocutaneous fistula 2 (6%) Bowel infarction 1 (3%) Renal failure 1 (3%)

closure. If tension exists, then a silo or mesh must be used for coverage [38].

mmHg prevents renal failure [45].

**Table 3.** Operative complications [44].

40 Respiratory Management of Newborns

resonance imaging [22].

After birth, the application of topical povidone-iodine, silver sulfadiazine or bacitracin ointment and xeroform gauze to the omphalocele sac allows epithelialization. Epithelialization often occurs within 10 weeks [16]. During this time, the infant can begin intestinal feeding.

As the giant omphalocele infant grows, the viscero-abdominal disproportion gradually resolves, but the infant must be clinically monitored. Giant omphalocele infants with respira‐ tory distress, pulmonary hypoplasia, pulmonary hypertension, or sepsis will require specific care strategies, until they meet the criteria for extubation. Surgical closure of the abdominal fascia is not a priority during this time period.

The respiratory status of some giant omphalocele infants improves to the point that they can be discharged, followed as an outpatient, and can return for elective closure [26]. When the omphalocele contents reduce manually into the abdominal cavity with ease, the body cavity is considered large enough to proceed with operative closure.

If the contents fit, the impact on venous return, renal perfusion, and diaphragmatic excursion is decreased. After operative closure, the majority of infants are extubated postoperatively, and the average length of hospital stay is 4 days. A minority of infants may have a longer ventilator time after closure (up to 21 days), and this can be difficult to predict [4, 26]. Parents should be informed of this possibility.

#### **9.2. Ruptured omphalocele**

A ruptured omphalocele is defined as any disruption of the omphalocele sac membrane [48]. Rupture of the omphalocele sac is frequently reported as a poor prognosticator associated with sepsis and mortality. The goal of the pediatric surgeon is to cover the eviscerated organs.

Although disrupted, if enough sac exists, it can be successfully sutured together with absorb‐ able sutures.

Successful reduction and coverage of a giant ruptured omphalocele are reported after silo placement and coverage with an absorbable mesh, followed by split thickness skin grafting [49]. Despite coverage, many infants die of respiratory insufficiency and infection [28].

A ruptured sac requires urgent surgical intervention, but only sporadic case reports exist that pertain to specific surgical management of a ruptured omphalocele.

Hemodynamic instability dominates the clinical course in infants with ruptured omphalocele. The majority of infants with ruptured omphalocele require at least 80 ml–1 kg–1 volume expansion in the first 7 days of life [38]. Intestinal exposure results in increased water and heat loss. Manipulation and closure can result in losses into a third space that exacerbates hypo‐ volemia.

Volume expansion to achieve a mean arterial pressure of 45 mmHg increases blood pressure and urine output. The use of renal dose dopamine is controversial, and benefits have not been confirmed in recent meta-analyses. High-dose norepinephrine should be avoided as it can exacerbate bowel ischemia and necrosis [38].

An infant with ruptured omphalocele requires surgical consultation to obtain organ coverage, but intensive cardiopulmonary support with features of sepsis and a high mortality rate will dominate the clinical course. The association between ruptured omphalocele, sepsis, and mortality is not well understood.

## **10. Long-term respiratory support**

There is a potential need for ongoing mechanical ventilatory support after the neonatal period in neonates born with a giant omphalocele. Partridge observed high rates of reactive airways disease in giant omphalocele survivors that was significantly associated with pulmonary hypertension [31]. Neonates with giant omphalocele and pulmonary hypertension required increased respiratory support based on the significant increases in the duration of mechanical ventilation, requirement for high-frequency oscillatory ventilation and tracheostomy, with dependence on home oxygen therapy following hospital discharge [31].

Whether reactive airways disease is an innate characteristic of the airways of infants with pulmonary hypoplasia associated with giant omphalocele versus increased respiratory support requirements and sequelae of mechanical ventilation remains unclear.

Pulmonary function abnormalities have been described in giant omphalocele survivors, and include reduced mean forced vital capacity and forced expiratory volume on pulmonary function testing with significant bronchodilator responsiveness in almost half of all patients studied [31]. Long-term respiratory issues in infants with giant omphaloceles include asthma, recurrent infections, chronic lung disease, and bronchomalacia.

Prolonged respiratory insufficiency is a frequent complication of giant omphalocele and the major prognostic factor for infants without life-threatening malformations. Infants with giant omphaloceles may require support for respiratory insufficiency into their second year of life. This possibility should be discussed with their families.

Of 22 long-term survivors with giant omphaloceles in a prospective follow-up series, chronic lung disease exists in 40%, and 16% have a tracheostomy for prolonged ventilation at a mean day of life 154 (median: 156 days; range: 100–204 days) [6]. Of six long-term survivors in a single retrospective series at 33.2 months (range: 20–70 months), three have asthma requiring medical therapy, two have recurrent infections, and one requires overnight continuous positive airway pressure (CPAP) at 20 months for bronchomalacia [4].

Not much data are reported about the indications of tracheostomy in neonates with giant omphalocele, although most retrospective series report a subset that required prolonged ventilation and tracheostomy placement, in general, 5–10% of infants in a series. In general, tracheostomies are placed to secure a safe airway for infants with protracted mechanical ventilation. The optimal timing for tracheostomy placement in these babies is unknown; however, severity of lung disease and problems of airway that preclude extubation are the most common indications.

There is no good evidence for deferring tracheostomy because infants are receiving high ventilator pressures. While high ventilator settings may be a concern that discourages consideration of tracheostomy placement, appropriate developmental interventions are nearly impossible to implement without placement of a tracheostomy in infants with an unstable artificial airway [50].

## **11. Gastroesophageal reflux disease (GERD)**

A ruptured sac requires urgent surgical intervention, but only sporadic case reports exist that

Hemodynamic instability dominates the clinical course in infants with ruptured omphalocele. The majority of infants with ruptured omphalocele require at least 80 ml–1 kg–1 volume expansion in the first 7 days of life [38]. Intestinal exposure results in increased water and heat loss. Manipulation and closure can result in losses into a third space that exacerbates hypo‐

Volume expansion to achieve a mean arterial pressure of 45 mmHg increases blood pressure and urine output. The use of renal dose dopamine is controversial, and benefits have not been confirmed in recent meta-analyses. High-dose norepinephrine should be avoided as it can

An infant with ruptured omphalocele requires surgical consultation to obtain organ coverage, but intensive cardiopulmonary support with features of sepsis and a high mortality rate will dominate the clinical course. The association between ruptured omphalocele, sepsis, and

There is a potential need for ongoing mechanical ventilatory support after the neonatal period in neonates born with a giant omphalocele. Partridge observed high rates of reactive airways disease in giant omphalocele survivors that was significantly associated with pulmonary hypertension [31]. Neonates with giant omphalocele and pulmonary hypertension required increased respiratory support based on the significant increases in the duration of mechanical ventilation, requirement for high-frequency oscillatory ventilation and tracheostomy, with

Whether reactive airways disease is an innate characteristic of the airways of infants with pulmonary hypoplasia associated with giant omphalocele versus increased respiratory

Pulmonary function abnormalities have been described in giant omphalocele survivors, and include reduced mean forced vital capacity and forced expiratory volume on pulmonary function testing with significant bronchodilator responsiveness in almost half of all patients studied [31]. Long-term respiratory issues in infants with giant omphaloceles include asthma,

Prolonged respiratory insufficiency is a frequent complication of giant omphalocele and the major prognostic factor for infants without life-threatening malformations. Infants with giant omphaloceles may require support for respiratory insufficiency into their second year of life.

Of 22 long-term survivors with giant omphaloceles in a prospective follow-up series, chronic lung disease exists in 40%, and 16% have a tracheostomy for prolonged ventilation at a mean

dependence on home oxygen therapy following hospital discharge [31].

recurrent infections, chronic lung disease, and bronchomalacia.

This possibility should be discussed with their families.

support requirements and sequelae of mechanical ventilation remains unclear.

pertain to specific surgical management of a ruptured omphalocele.

exacerbate bowel ischemia and necrosis [38].

**10. Long-term respiratory support**

mortality is not well understood.

42 Respiratory Management of Newborns

volemia.

In infants with omphaloceles, the incidence of gastroesophageal reflux disease (GERD) with associated esophagitis approaches 45% [51]. Gastroesophageal reflux disease is diagnosed at a median age of 7 months and is more prevalent in infants with giant defects. Infants with omphalocele and a large defect have a high incidence of GERD complicated by esophagitis during the first few years of life [51].

Frequently, the retrospective series reports infants with omphaloceles and GERD that fail medical therapy and undergo Nissen fundoplication [6].