**3.1 Mechanical ventilation**

Mechanical ventilation is the most commonly applied treatment method for NRDS in clinical practice [37–39]; although mechanical ventilation and continuous oxygen therapy are independent risk factors for development of NRDS to bronchopulmonary dysplasia (BPD) [40, 41]. Noninvasive respiratory support methods such as nasal intermittent positive pressure ventilation (NIPPV), high flow nasal cannula (HFNC) and nasal continuous positive airway pressure (NCPAP) are being used more commonly as the initial ways of management, which may decrease need for intubation in up to 50% of infants [42–44]. On the other hand, the failure of noninvasive respiratory support results in delayed administration of surfactant and prolonged mechanical ventilation. Also, this may be associated with higher incidence of bronchopulmonary dysplasia (BPD), major morbidity or even death [45, 46]. So, it seems that a combination of early respiratory support and prescription of surfactant may improve the treatment results. Administration of surfactant during NCPAP, less-invasive (LISA) and minimalinvasive surfactant administration (MISA) have shown convenient results in management of NRDS [47].

Recently published studies have introduced the aerosolized surfactant as a safe and efficient method of drug delivery [47]. It has been claimed that vibrating and ultrasonic mesh nebulizers have the ability to make surfactant aerosols without interfering with biochemical composition of medication [48–50]. It has been reported that aerosolized surfactant can be delivered using nasal cannula in noninvasive respiratory support [51–55].

### **3.2 Surfactant**

Pathophysiology of NRDS (inadequate production of pulmonary surfactant in premature infants) was first discovered by Avery and Mead in 1959, which resulted in changing the former name of the disease "hyaline membrane disease" [56]. This was a window to surfactant replacement therapy.

Lung surfactant is a mixture of phospholipids and some specific proteins secreted by epithelium of alveoli, which lines the small airways. It primarily reduces the surface tension of liquid presented in terminal air spaces [57]. Lack of pulmonary surfactant is the main result of NRDS; so, prescription of pulmonary surfactant can augment respiratory function and pulmonary compliance resulting in elevated oxyhemoglobin level [58–61]. Lack of surfactant results in a chain of problems from collapsed lung, tissue damage, reduced oxygenation and impaired function of alveolar epithelium, resulting in altered production of surfactant [62]. Fujiwara et al. reported the very first application of surfactant-TA in preterm infants with respiratory distress syndrome in 1980 [63].

There are different kinds of animal-derived as well as first- and second-generation synthetic surfactants [64]. As a natural surfactant, Curosurf is taken from pig lung, which is consisted of 41–48% lecithin and 51–58% of hydrophobin and other phospholipids. Liquid gel layer has the responsibility to absorb the Curosurf after its administration to the lungs [65]. Also, this medication has some adverse effects including respiratory discomforts and bucking [66, 67]. Administration of surfactant involves frequent endotracheal intubation (INSURE: INtubation-SURfactant-Extubation) and mechanical ventilation, which is associated with inevitable comorbidities [68, 69].

**23**

*Neonatal Respiratory Distress Syndrome: Things to Consider and Ways to Manage*

Recently, in addition to the common INSURE method, a new method has come up and is getting more popular. This method is called a less-invasive surfactant administration (LISA), which has been reported to be more effective in prevention of bronchopulmonary dysplasia and reducing preterm infants' mortality. In this method, surfactant is delivered through a thin catheter while the infant is under continuous positive airway pressure (CPAP) treatment. However, more large-scale randomized clinical trials are needed to make this method accepted as a routine in

As an active metabolite of bromhexine, ambrotherxol or ambroxol hydrochloride has a mucolytic activity. A wide range of advantages have been reported for ambroxol hydrochloride from reducing production of hydrogen peroxide, stimulating secretion of pulmonary surfactant, reducing lung damage and alleviating the inflammatory response to relieving pulmonary edema and interstitial exudation. As a low-cost and high-efficacy medication, ambroxol hydrochloride is being used in clinical treatment of NRDS [71, 72]. There are reports about satisfactory results of

combination of high-dose ambroxol hydrochloride and surfactant [37].

About 2% of all live births are involved with respiratory failure, which is responsible for more than one-third of neonatal mortalities [73]. Inhaled NO (iNO) reduces pulmonary vascular resistance, edema, lung inflammation and hypoxia, which makes the respiratory difficulties easier for infants [74]. Previous researches have also shown that iNO improves pulmonary angiogenesis and protects pulmonary system against infections with no remarkable adverse effects on growth or

Neonatal respiratory distress syndrome (NRDS), as a result of inadequate surfactant production, leads to atelectasis and ventilation-perfusion (V/Q ) mismatching. Beside notable response to exogenous surfactant, it has been reported that iNO transiently improves oxygenation in infants with NRDS. Previous studies have shown that iNO therapy alone reduces mortality rate in preterm infants [76]. iNO improves V/Q matching, selectively dilates the pulmonary vasculature and decreases pulmonary inflammatory response. The most convenient advantage of iNO is reducing incidence of chronic lung disease in premature infants with RDS [77]. In other researches, premature infants with suboptimal response to exogenous surfactant showed beneficial clinical responses to combination therapy

Neonatal respiratory distress syndrome is one of the major causes of premature death; however, a notable part of the survivors may develop bronchopulmonary dysplasia and suffer from chronic pulmonary diseases [67]. Prognosis of RDS is highly related to the treatment and management methods, which have been being developed since their discovery. The efficacy of each method for prognosis is under investigation. Also, gestational age has an important role in determining the prognosis, where late preterm infants usually have a better prognosis in comparison

*DOI: http://dx.doi.org/10.5772/intechopen.90885*

clinical practice [70].

*3.3.1 Nitric oxide (NO)*

with iNO [78].

**4. Prognosis**

with early preterm infants.

neurodevelopmental status [75].

**3.3 Ambroxol hydrochloride**

*Neonatal Respiratory Distress Syndrome: Things to Consider and Ways to Manage DOI: http://dx.doi.org/10.5772/intechopen.90885*

Recently, in addition to the common INSURE method, a new method has come up and is getting more popular. This method is called a less-invasive surfactant administration (LISA), which has been reported to be more effective in prevention of bronchopulmonary dysplasia and reducing preterm infants' mortality. In this method, surfactant is delivered through a thin catheter while the infant is under continuous positive airway pressure (CPAP) treatment. However, more large-scale randomized clinical trials are needed to make this method accepted as a routine in clinical practice [70].

#### **3.3 Ambroxol hydrochloride**

*Update on Critical Issues on Infant and Neonatal Care*

Mechanical ventilation is the most commonly applied treatment method for NRDS in clinical practice [37–39]; although mechanical ventilation and continuous oxygen therapy are independent risk factors for development of NRDS to bronchopulmonary dysplasia (BPD) [40, 41]. Noninvasive respiratory support methods such as nasal intermittent positive pressure ventilation (NIPPV), high flow nasal cannula (HFNC) and nasal continuous positive airway pressure (NCPAP) are being used more commonly as the initial ways of management, which may decrease need for intubation in up to 50% of infants [42–44]. On the other hand, the failure of noninvasive respiratory support results in delayed administration of surfactant and prolonged mechanical ventilation. Also, this may be associated with higher incidence of bronchopulmonary dysplasia (BPD), major morbidity or even death [45, 46]. So, it seems that a combination of early respiratory support and prescription of surfactant may improve the treatment results. Administration of surfactant during NCPAP, less-invasive (LISA) and minimalinvasive surfactant administration (MISA) have shown convenient results in

Recently published studies have introduced the aerosolized surfactant as a safe and efficient method of drug delivery [47]. It has been claimed that vibrating and ultrasonic mesh nebulizers have the ability to make surfactant aerosols without interfering with biochemical composition of medication [48–50]. It has been reported that aerosolized surfactant can be delivered using nasal cannula in nonin-

Pathophysiology of NRDS (inadequate production of pulmonary surfactant in premature infants) was first discovered by Avery and Mead in 1959, which resulted in changing the former name of the disease "hyaline membrane disease" [56]. This

There are different kinds of animal-derived as well as first- and second-generation synthetic surfactants [64]. As a natural surfactant, Curosurf is taken from pig lung, which is consisted of 41–48% lecithin and 51–58% of hydrophobin and other phospholipids. Liquid gel layer has the responsibility to absorb the Curosurf after its administration to the lungs [65]. Also, this medication has some adverse effects including respiratory discomforts and bucking [66, 67]. Administration of surfactant involves frequent endotracheal intubation (INSURE: INtubation-SURfactant-Extubation) and mechanical ventilation, which is associated with inevitable

Lung surfactant is a mixture of phospholipids and some specific proteins secreted by epithelium of alveoli, which lines the small airways. It primarily reduces the surface tension of liquid presented in terminal air spaces [57]. Lack of pulmonary surfactant is the main result of NRDS; so, prescription of pulmonary surfactant can augment respiratory function and pulmonary compliance resulting in elevated oxyhemoglobin level [58–61]. Lack of surfactant results in a chain of problems from collapsed lung, tissue damage, reduced oxygenation and impaired function of alveolar epithelium, resulting in altered production of surfactant [62]. Fujiwara et al. reported the very first application of surfactant-TA in preterm

**3. Management**

**3.1 Mechanical ventilation**

management of NRDS [47].

vasive respiratory support [51–55].

was a window to surfactant replacement therapy.

infants with respiratory distress syndrome in 1980 [63].

**3.2 Surfactant**

**22**

comorbidities [68, 69].

As an active metabolite of bromhexine, ambrotherxol or ambroxol hydrochloride has a mucolytic activity. A wide range of advantages have been reported for ambroxol hydrochloride from reducing production of hydrogen peroxide, stimulating secretion of pulmonary surfactant, reducing lung damage and alleviating the inflammatory response to relieving pulmonary edema and interstitial exudation. As a low-cost and high-efficacy medication, ambroxol hydrochloride is being used in clinical treatment of NRDS [71, 72]. There are reports about satisfactory results of combination of high-dose ambroxol hydrochloride and surfactant [37].

### *3.3.1 Nitric oxide (NO)*

About 2% of all live births are involved with respiratory failure, which is responsible for more than one-third of neonatal mortalities [73]. Inhaled NO (iNO) reduces pulmonary vascular resistance, edema, lung inflammation and hypoxia, which makes the respiratory difficulties easier for infants [74]. Previous researches have also shown that iNO improves pulmonary angiogenesis and protects pulmonary system against infections with no remarkable adverse effects on growth or neurodevelopmental status [75].

Neonatal respiratory distress syndrome (NRDS), as a result of inadequate surfactant production, leads to atelectasis and ventilation-perfusion (V/Q ) mismatching. Beside notable response to exogenous surfactant, it has been reported that iNO transiently improves oxygenation in infants with NRDS. Previous studies have shown that iNO therapy alone reduces mortality rate in preterm infants [76]. iNO improves V/Q matching, selectively dilates the pulmonary vasculature and decreases pulmonary inflammatory response. The most convenient advantage of iNO is reducing incidence of chronic lung disease in premature infants with RDS [77]. In other researches, premature infants with suboptimal response to exogenous surfactant showed beneficial clinical responses to combination therapy with iNO [78].

### **4. Prognosis**

Neonatal respiratory distress syndrome is one of the major causes of premature death; however, a notable part of the survivors may develop bronchopulmonary dysplasia and suffer from chronic pulmonary diseases [67]. Prognosis of RDS is highly related to the treatment and management methods, which have been being developed since their discovery. The efficacy of each method for prognosis is under investigation. Also, gestational age has an important role in determining the prognosis, where late preterm infants usually have a better prognosis in comparison with early preterm infants.
